Brain-Derived Neurotropic Factor in Neurodegenerative Disorders

Abstract

Globally, neurodegenerative diseases cause a significant degree of disability and distress. Brain-derived neurotrophic factor (BDNF), primarily found in the brain, has a substantial role in the development and maintenance of various nerve roles and is associated with the family of neurotrophins, including neuronal growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5). BDNF has affinity with tropomyosin receptor kinase B (TrKB), which is found in the brain in large amounts and is expressed in several cells. Several studies have shown that decrease in BDNF causes an imbalance in neuronal functioning and survival. Moreover, BDNF has several important roles, such as improving synaptic plasticity and contributing to long-lasting memory formation. BDNF has been linked to the pathology of the most common neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. This review aims to describe recent efforts to understand the connection between the level of BDNF and neurodegenerative diseases. Several studies have shown that a high level of BDNF is associated with a lower risk for developing a neurodegenerative disease.

Full text

Citation: Ibrahim, A.M.; Chauhan, L.;
Bhardwaj, A.; Sharma, A.; Fayaz, F.;
Kumar, B.; Alhashmi, M.; AlHajri, N.;
Alam, M.S.; Pottoo, F.H.
Brain-Derived Neurotropic Factor in
Neurodegenerative Disorders.
Biomedicines 2022,10, 1143.
https://doi.org/10.3390/
biomedicines10051143
Academic Editor: Marco Segatto
Received: 13 February 2022
Accepted: 30 April 2022
Published: 16 May 2022
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biomedicines
Review
Brain-Derived Neurotropic Factor in
Neurodegenerative Disorders
Abdallah Mohammad Ibrahim 1, Lalita Chauhan 2, Aditi Bhardwaj 3, Anjali Sharma 4, Faizana Fayaz 4,
Bhumika Kumar 5, Mohamed Alhashmi 6, Noora AlHajri 7, * , Md Sabir Alam 8and Faheem Hyder Pottoo 9, *
1Department of Fundamentals of Nursing, College of Nursing, Imam Abdul Rahman Bin Faisal University,
Dammam 31441, Saudi Arabia; amsudqi@iau.edu.sa
2School of Pharmacy & Emerging Sciences, Baddi University of Emerging Sciences & Technology,
Baddi 173205, India; lalitachauhan004@gmail.com
3Department of Pharmaceutical Sciences, Manav Bharti University, Vill. Laddo, Sultanpur (Kumarhatti),
Solan 173229, India; aadipharma53@gmail.com
4
Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Sector-3,
MB Road, Pushp Vihar, New Delhi 110017, India; anjalish092@gmail.com (A.S.);
faizanazargar@gmail.com (F.F.)
5Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Sector-3, MB Road,
Pushp Vihar, New Delhi 110017, India; bhumika201993@gmail.com
6College of Medicine and Health Sciences, Khalifa University,
Abu Dhabi P.O. Box 127788, United Arab Emirates; 100053507@ku.ac.ae
7Department of Medicine, Sheikh Shakhbout Medical City (SSMC),
Abu Dhabi P.O. Box 127788, United Arab Emirates
8SGT College of Pharmacy, SGT University, Gurgaon 122505, India; mdsabiralam86@gmail.com
9Department of Pharmacology, College of Clinical Pharmacy, Imam Abdul Rahman Bin Faisal University,
P.O. Box 1982, Dammam 31441, Saudi Arabia
*Correspondence: nalhajri007@gmail.com (N.A.); fhpottoo@iau.edu.sa (F.H.P.)
Abstract:
Globally, neurodegenerative diseases cause a significant degree of disability and distress.
Brain-derived neurotrophic factor (BDNF), primarily found in the brain, has a substantial role
in the development and maintenance of various nerve roles and is associated with the family of
neurotrophins, including neuronal growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5
(NT-4/5). BDNF has affinity with tropomyosin receptor kinase B (TrKB), which is found in the brain
in large amounts and is expressed in several cells. Several studies have shown that decrease in BDNF
causes an imbalance in neuronal functioning and survival. Moreover, BDNF has several important
roles, such as improving synaptic plasticity and contributing to long-lasting memory formation.
BDNF has been linked to the pathology of the most common neurodegenerative disorders, such as
Alzheimer’s and Parkinson’s disease. This review aims to describe recent efforts to understand the
connection between the level of BDNF and neurodegenerative diseases. Several studies have shown
that a high level of BDNF is associated with a lower risk for developing a neurodegenerative disease.
Keywords:
brain-derived neurotrophic factor; tropomyosin receptor kinase B; neurodegenerative
disorders; Alzheimer’s disease; Parkinson’s disease
1. Introduction
In the central nervous system, brain-derived neurotrophic factor (BDNF) is a signifi-
cant neurotrophic factor with a major role in neuronal cell differentiation, maturation [
1
],
and survival [
2
]. BDNF also has a neuroprotective effect in several pathological condi-
tions, including cerebral ischemia, glutamatergic stimulation, decreased blood glucose,
and neurotoxicity [
3
]. It promotes and regulates neurogenesis [
4
] in several regions in the
central nervous system, such as the cerebral cortex, olfactory system, mesencephalon, basal
forebrain, hippocampus, hypothalamus, spinal cord, and the brainstem [
1
]. Low levels of
BDNF protein have been shown to have a role in the development of neurodegenerative
Biomedicines 2022,10, 1143. https://doi.org/10.3390/biomedicines10051143 https://www.mdpi.com/journal/biomedicines

Biomedicines 2022,10, 1143 2 of 18
disorders, such as Parkinson’s disease (PD) [
5
], multiple sclerosis (MS) [
6
], and Hunting-
ton’s disease [
7
]. Additionally, BDNF plays a major role in energy homeostasis along with a
neuroprotective effect, and has been shown to be able to restrain calorie intake and decrease
body weight via peripheral or intracerebroventricular (ICV) administration [8].
BNDF can also be found in the peripheral tissues as it can cross the blood-brain barrier;
this peripheral circulating BDNF is not derived from the brain, but can be synthesized
in several tissues including the liver, lung, muscles, spleen, and the vascular smooth
muscles. Most of the peripheral BDNF is stored inside the platelets while the remaining
amount circulates in the plasma. It has been suggested that the level of peripheral BDNF is
correlated and regulated by the level of CNS BDNF [9].
According to modern estimates, neurological diseases are major contributors to dis-
ability and morbidity, and the percentage of disease occurrence is predicted to be higher in
the future [
10
,
11
]. The absence of adequate therapy means that such diseases create consid-
erable problems worldwide. The lack of adequate therapy is partially due to insufficient
awareness or knowledge about the causes of most neurological disorders. Many diseases
related to the central nervous system are closely connected to various environmental stim-
uli, such as stress [
12
]. Challenging events create severe risks for people with such diseases,
particularly those who are more susceptible to the effects of the disease. A high level of
stress sometimes has beneficial effects, such as increased attention and memory. However,
stress can have harmful effects on the brain when disquieting actions become part of the
daily life of an individual [
13
]. Various studies have shown that strain is related to metabolic
problems, increased risk of heart disease, damage to endocrine functions, fluctuations in
mood, and impairment of mental abilities. Stress also leads to greater risk of development
of manic and neurologic disorders [
13
]. Persistent strain causes activation of microglia
and increases the secretion of cytokines and pro-inflammatory mediators, leading to the
migration of various immune cells into brain tissue, thus creating a suitable environment
for the development of numerous brain diseases. In response to sustained stress, brain
cells secrete several anti-inflammatory mediators, growth factors, and neurotrophic factors
that can help neuronal survival [
14
]. BDNF has been suggested to be an important factor
in various pathological conditions and is a candidate biomarker in therapies of various
neuronal diseases [
15
]. In blood, BDNF levels significantly change in response to current
treatments; therefore, it is difficult to completely understand the processes that support
alteration in BDNF levels in the diseased state [
15
], and that reduce BDNF in the CNS and
blood [
16
]. In summary, BDNF has a significant role in the pathology of many neurological
diseases, with inflammation of neurons serving as a primary trigger for the development
of brain pathologies [16,17].
2. BDNF Expression
BDNF is the fourth member of the neurotrophin family that consists of four structurally
related factors which also include neuronal growth factors (NGF), neurotrophin 3 (NT-3)
and neurotrophin 4 (NT-4). The gene that encodes BDNF includes 3
0
region exons that
contain the code of the pro-BDNF proteins, and, in the 5
0
region, a promoter region that
terminates in the 5
0
-exon which influences gene expression [
16
,
17
]. The gene consists of
five exons with the coding region found entirely on exon V; the other four exons have
the promotor region on their 5
0
flanking region, and, at the 3
0
end, contain a splice donor.
Exon V has a splice acceptor on the 5
0
region and on the 3
0
end it has two polyadenylation
sites. Therefore, each one of the four exons can have alternative splicing with exon V
with the adenylation sites able to produce eight different transcripts of the BDNF [
18
].
Several experiments have shown that the 5
0
region in the four exons has different responses
according to various neuronal activities, as both hippocampal and cortical activities can
regulate the transcripts that contain exon III [
19
]. It is thought that the structure of the
BDNF gene is related to the stage of development, the type of tissue and the function of
the BDNF protein in cellular localization. Despite the similarity of the BDNF gene across
different species, there are certain structural differences that are dependent on the specific

Biomedicines 2022,10, 1143 3 of 18
function of BDNF in that organism [
20
]. The gene expression of BDNF is regulated at a high
level by a wide range of external and internal factors, such as the level of stress, degree of
exercise and activity, brain injury, and food [
21
]. The level of BDNF expression was found
to be very low during fetal development but to increase significantly after birth followed
by another decline in expression in adulthood. BDNF is expressed throughout the entire
brain with the highest levels found in hippocampal and cerebellar regions [22,23].
BDNF gene translation produces a proneurotrophin (pro-BDNF) [
24
]. Subsequently,
the pro-BDNF protein is cleaved by endoproteases in the cytoplasm to produce the mature
BDNF or by plasmin or matrix metalloproteinases (MMP) which occur in the extracellular
matrix [
25
]. Then, the mature and pro-BDNF are secreted and are bound to the p75
neurotrophin receptor (p75NTR) triggering an apoptosis cascade [
26
]. On the opposite
side, cleaved mature BDNF binds to the tyrosine kinase B (TrkB) receptor which is of
higher affinity. Binding to the receptor triggers various signaling cascades that include the
Ras-mitogen-activated protein kinase (MAPK), the phosphatidylinositol-3-kinase (PI3K),
and the phospholipase C
γ
(PLC-
γ
) pathway [
27
]. These pathways increase the influx of
Ca
2+
which leads to activation of transcription factors by phosphorylation and increased
BDNF gene expression (Figure 1) [27].
Biomedicines 2022, 10, x FOR PEER REVIEW 3 of 18
gene is related to the stage of development, the type of tissue and the function of the BDNF
protein in cellular localization. Despite the similarity of the BDNF gene across different
species, there are certain structural differences that are dependent on the specific function
of BDNF in that organism [20]. The gene expression of BDNF is regulated at a high level
by a wide range of external and internal factors, such as the level of stress, degree of exer-
cise and activity, brain injury, and food [21]. The level of BDNF expression was found to
be very low during fetal development but to increase significantly after birth followed by
another decline in expression in adulthood. BDNF is expressed throughout the entire
brain with the highest levels found in hippocampal and cerebellar regions [22,23].
BDNF gene translation produces a proneurotrophin (pro-BDNF) [24]. Subsequently,
the pro-BDNF protein is cleaved by endoproteases in the cytoplasm to produce the mature
BDNF or by plasmin or matrix metalloproteinases (MMP) which occur in the extracellular
matrix [25]. Then, the mature and pro-BDNF are secreted and are bound to the p75 neu-
rotrophin receptor (p75NTR) triggering an apoptosis cascade [26]. On the opposite side,
cleaved mature BDNF binds to the tyrosine kinase B (TrkB) receptor which is of higher
affinity. Binding to the receptor triggers various signaling cascades that include the Ras-
mitogen-activated protein kinase (MAPK), the phosphatidylinositol-3-kinase (PI3K), and
the phospholipase Cγ (PLC-γ) pathway [27]. These pathways increase the influx of Ca
2+
which leads to activation of transcription factors by phosphorylation and increased BDNF
gene expression (Figure 1) [27].
Figure 1. The figure shows the pathways by which BDNF signals can promote the survival of neu-
ronal cells. The binding of BDNF to TrkB receptor switches on 3 different signaling pathways: the
first pathway is the activation of the (PLC-γ) pathway which increases the level of Ca
2+
that will
Figure 1.
The figure shows the pathways by which BDNF signals can promote the survival of
neuronal cells. The binding of BDNF to TrkB receptor switches on 3 different signaling pathways:
the first pathway is the activation of the (PLC-
γ
) pathway which increases the level of Ca
2+
that will

Biomedicines 2022,10, 1143 4 of 18
terminate the apoptosis that is caused by inflammatory mediators (dashed lines), achieved by
inhibiting the glycogen synthase kinase 3-beta (GSK-3
β
). The second pathway is activation of
mTOR-dependent translation through the (PI3K) pathway, resulting in the transcription of BDNF
mRNA. Additionally, the induction of Akt and Erk downstream enhances gene regulation through
the NF-
κ
B and CREB transcription factors. The third pathway is regulated by several factors such
as zinc, epidermal growth factor, glucocorticoids, and the so called neurotrophic pathway, which is
considered to be independent for BDNF as it can transactivate the TrkB and has a role in its signaling.
This figure is adapted after modification from open access [10].
Although pro-BDNF can activate the apoptosis pathway, it is not known if it is secreted
by neuronal cells under normal circumstances because the concentration of the pro-BDNF
is less than that of mature BDNF [
10
]. This has been demonstrated in animal research which
showed that the mature BDNF concentration was ten times more than the concentration
of pro-BDNF [
28
]. This raises the issue of whether pro-BDNF is an effective factor for
signaling. BDNF function is widespread in multiple regions within the brain [
21
]. The
function of BDNF includes participation in neuronal plasticity, the survival of neuronal
cells, the synthesis of new synapses, the branching of dendritic cells, and the adjustment of
neurotransmitter activity between excitation and inhibition [
29
]. The activity of BDNF is
seen during all developmental stages and within different age groups [30].
These observations suggest that BDNF and pro-BDNF have opposite biological activity;
thus, post-transitional control and how pro-BDNF is processed can have an important
influence on the biological activity of BDNF [
31
]. A significant change in the BDNF function
could be achieved by the process of adding a pro-domain to the gene of BDNF. This pro-
domain has a role in the folding of the BDNF protein [
32
]. Genetic polymorphism in the
pro-domain that arises from a valine to methionine substitution in the 66 codons (Val66Met)
results in a change in memory function and affects the BDNF secretion process [
33
]. This
suggests that the pro-domain region is the area which contains most of the function in the
gene for BDNF [
31
]. In transgenic mice where the mutation Val66Met was induced, altered
anxiety behavior was expressed [
34
] as well as alteration in NMDR-dependent neuronal
plasticity in the hippocampus region [
35
]. Experiments performed on hippocampal slices
from transgenic mice showed that if mice were injected with BDNF pro-peptide it inhibited
LTD in the hippocampus [
36
]. BDNF’s role in transmission at synapses requires further
investigation—many pieces of research suggest that it has a significant role in enhancing
the efficacy of synaptic transmission in the hippocampus and the cortex [
37
,
38
]. Supporting
evidence has included the administration of K252a, which is a TrK receptor inhibitor, or
TrKB-IgG, which resulted in the prevention of the induction of long-term potentiation in
these areas [39].
3. Pathological Mechanism of Action
BDNF and NT-4/5 can bind to the TrkB receptor, in contrast to NGF, which can bind
to several receptors, such as Trk A, C subtypes, and NT-3 [
40
]. TrkB occurs in two similar
forms: a full-length type, abbreviated to Gp145 TrkB, with a molecular weight of 145 kDa,
and a truncated form, abbreviated as Gp95 TrkB, with a molecular weight of 95 kDa. The
truncated form differs from the full length form in that it lacks the tyrosine kinase domain
and shows lower affinity to the nerve growth factor receptor (LNGFR); it is denoted p75
NTR [
41
]. LNGFR is involved in processes that are pro- and anti-trophic, such as neuron
growth and death. BDNF and gp145TrkB have broad expression in brain cells; BDNF
receptors are also found in the spinal cord, specifically the gray matter neurons [42].
3.1. Activation of TrkB
The signaling of neurotrophin has a significant role in maintaining the survival and
proliferation of cells, the reduction of neural precursors, and axon and dendrite growth via
TrkB receptors [
43
]. The NTRK2 gene encodes for neurotrophic tyrosine kinase in human
beings [
43
,
44
]. TrkB has extracellular domains with multiple glycosylation sites and a
transmembrane area with an intracellular domain that has Trk activity. Once activated, G

Biomedicines 2022,10, 1143 5 of 18
proteins, such as Ras and MAP kinase, regulate the PI3-kinase and phospholipase-C-
γ
(PLC-
γ
) pathways [
45
]. Signal activation is faster than deactivation; activation needs two minutes,
while the deactivation requires around thirty minutes in the spinal cord. Trk signals are
regulated by various mediators [
40
,
43
]. Nonetheless, other small G protein messengers
have a significant role in BDNF signaling, such as Ras, Rap-1, and Cdc-42-Ra [2].
3.2. Secondary Messengers Activation
The Trk receptor family (which includes TrkA-C) and LNGFR regulate the function of
the different types of neurotrophins. The pre-synaptic p75 NTR plays a role in regulating
the binding to the Trk receptor, ERK activation by Ras, neurite protuberance and activation
of terminal kinase (JNK), which causes apoptosis in different neuronal cells [
2
]. BDNF
signaling activates various secondary messengers in the spinal cord, including via ERK
signaling, the proto-oncogene c-fos, and neurons that produce nitric oxide [2,46].
3.3. Signaling Cascade in BDNF
Tyrosine residue activation by BDNF leads to the stimulation of pathways that affect
neural plasticity, neurogenesis, cell survival, and resistance to stress, which shows the
pro-survival function of Trk receptors. BDNF signaling results in the activation of several
transcription factors, such as CREB and the CREB-binding protein (CBP), which modulate
gene expression that encodes several proteins which participate in different neuronal
functions, such as the plasticity of neurons, neuron response to stress, and survival of
neurons [43,47,48].
3.4. Ras/MAPK/ERK Pathway
Activation of the TrkB receptor by BDNF leads to dimerization of the receptor and
phosphorylation of tyrosine residues; this creates a site for the src-homology domain which
contains the Shc adaptor protein and phospholipase C(PLC). The Shc binds to both the
receptor and the protein Grb2 through the nucleotide releasing factor SOS. This leads to
activation of RAS [49].
Ras activation stimulates the Ras/MAPK-ERK pathway, PI3-K pathway, and PLC
pathway. MAPK/ERK is essential for the formation and survival of neurons by activating
several genes responsible for the survival of the neurons and inhibition of apoptosis [
50
].
Research concerning immature neuronal cells showed that activation of the RAS protein
via BDNF protected the neurons from MK801-induced apoptosis [
51
]. In diseases such as
schizophrenia, very low levels of ERK signaling proteins in the prefrontal cortex have been
observed [52].
3.5. IRS-1/PI3K/AKT Pathway
Other pathways that participate in the actions of BDNF are insulin receptor activation,
substrate-1 (IRS-1/2), PI-3K, and protein kinase B (Akt). Ras stops apoptosis by PI3K that
activates pkB via deposition of the protein involved in the apoptosis pathway away from
their targets [
50
]. Thus, the Ras-PI3K-Akt pathway is crucial for the survival of neuronal
cells, and any deactivation of this pathway will reduce neuronal survival [
53
]. BDNF
can protect hippocampus neurons from the effects of glutamate and norepinephrine via
this pathway. In the hippocampus, BDNF autocrine loops result in low stimulation of
NMDA receptors which means low glutamate effects and excitotoxicity [
54
]. Evidence
from postmortem studies indicated the relationship between alteration in the Akt and Erk
signaling pathways and schizophrenia; there was a low level of AKT1 mRNA proteins in
the cortex and the hippocampus [
55
], and there were some genetic variants of the AKT1
gene0020 that have been linked to schizophrenia [56].
3.6. PLC/DAG/IP3 Pathway
The binding of BDNF to the Trk receptor initiates phosphorylation of the PLC-
γ
protein
that leads to membrane lipids being broken down into inositol 1,4,5 triphosphate (IP3) and

Biomedicines 2022,10, 1143 6 of 18
diacylglycerol (DAG) [
57
], with the former inducing calcium influx and later activating
protein kinase C which is needed for neurite outgrowth [58,59].
4. Functions of BDNF
BDNF has generally been recognized in humans as a protein compressed from the
BDNF gene. BDNF was initially isolated from the pig [
58
]. BDNF is the foremost neu-
rotrophic factor that has been discovered [
60
]. It acts via the protein tyrosine kinase receptor
(TrkB) [61] and is generally associated with aspects of nerve growth [49].
BDNF plays a crucial part in the process of neuro-regeneration [
62
,
63
] by preventing
neuronal death particularly in the peripheral nervous system [
64
]. It helps to promote
the growth of immature neurons and increases the efficiency of adult neurons [65]. Inside
the brain, the role of BDNF is essential for the mediation of synaptic function and the
morphology of the neurons rather than being a survival factor [
66
,
67
]. Furthermore,
BDNF plays a significant part in memory function as it has a role in the formation of
memory [
29
], synaptic plasticity [
68
], synapse formation [
69
], synaptic efficacy and neuronal
connectivity [
70
]. In the striatum, the loss of BDNF signalling results in spinal atrophy,
which is caused by a defect in the GABAergic spiny neuron in the striatum [
71
]; striatum
GABAergic neurons do not produce BDNF, but they obtain it from the presynaptic neurons
of the cortico-striatal projections [
30
]. Disruption in the axonal BDNF transport to the
striatum from reduced cortical supply results in the degeneration of striatal neurons, a
pathological feature of Huntington’s disease [
72
]. BDNF in the periphery exists in the
plasma, platelets, and the serum [
73
]. The formation of BDNF is generally performed by
vascular endothelial cells and secondary blood mononuclear cells [
74
]. Observations of
polymeric markers has demonstrated an association of bipolar disorder with BDNF in large
samples, particularly the Neves-Pereira samples [75,76].
Animal studies have shown that neurotrophins are found in high concentrations in
the hippocampus and the hypothalamus, suggesting a significant role of BDNF in learning
and memory [
21
,
77
]. The decline observed during aging involves multiple factors that
influence several systems. In the case of learning and memory processes which are severely
reduced with aging, it has been found that these cognitive effects result from impaired
neuronal plasticity, which is altered in normal aging but particularly so in Alzheimer’s
disease. Neurotrophins and their receptors, notably BDNF, are expressed in brain areas
exhibiting a high degree of plasticity (i.e., the hippocampus, cerebral cortex) and are con-
sidered as molecular mediators of functional and morphological synaptic plasticity. The
modification of BDNF and/or the expression of its receptors (TrkB.FL, TrkB.T1 and TrkB.T2)
have been described during normal aging and in Alzheimer’s disease. Interestingly, recent
findings have shown that some physiological or pathologic age-associated changes in the
central nervous system could be offset by administration of exogenous BDNF and/or by
stimulating its receptor expression. These molecules may thus represent a physiological
reserve which could determine physiological or pathological aging. These data suggest
that boosting the expression or activity of these endogenous protective systems may be a
promising therapeutic alternative to enhance healthy aging [
21
,
78
,
79
]. With aging, reduc-
tion in neuronal plasticity in the hippocampus and the hypothalamus leads to impairment
in learning and memory function [
80
]. BDNF participates in synaptic plasticity and can
protect the neuron from several brain insults [
81
]. A systematic review and meta-analysis
conducted in 2019 found that patients with Alzheimer’s disease have lower levels of BDNF,
especially during the late stages of the disease [
82
]. Furthermore, BDNF plays an important
role in learning and memory formation; El Hayek et al. found that during exercise in
male mice, lactate metabolite enhanced hippocampal-dependent learning via the BDNF
pathway [83].
Administration of a single dose of BDNF into the hippocampus resulted in improve-
ment in memory and emotional behaviour in rats [
84
], while chronic administration of
BDNF was shown to have positive potentiation effect in neurotransmission in the hip-
pocampus region [
85
]. Moreover, a strong connection between the level of BDNF mRNA in

Biomedicines 2022,10, 1143 7 of 18
the hippocampus and the memory function has been reported in rats [
86
]. In the hypotha-
lamus, BDNF can participate in a neurohormonal role via the induction of synthesis, and
the release of these hormones [
87
,
88
], while the expression of BDNF varies in response to
different physiological stimuli [89].
4.1. BDNF and Aging
Aging is a process that consists of multiple declines in endocrine, cognitive, and
immunological functions. Several factors play a major role in determining the aging
process and the outcome, such as genetic, epigenetic, and environmental factors [
90
]. In
most cases, there is a decline in cognitive capabilities linked to altered hippocampal and
cortical functions [
91
]. Moreover, memory is affected significantly by the aging process,
though the degree of memory impairment varies between individuals and the types of
memory involved [
92
]. Generally, effective cognitive function is associated with optimal
neural plasticity that is markedly decreased with aging [
93
]. Change in learning function is
not usually associated with neuron loss [
94
]. The cognitive and learning function changes
have been correlated to decreased BDNF expression and signaling [
94
]. There is impairment
in BDNF-induced LTP due to changes in receptor function, which has been attributed to
age-related effects.
The administration of Ampakine can induce expression of BDNF, which can revert
changes in the neuronal plasticity function, as observed by some researchers [
95
]. Ampakine
modulates AMPA receptors that can restore LTP to the basal dendrites, which is shown to
improve memory function in rats [
96
]. Certain environmental influences can reverse the
decline in hippocampal plasticity and reduced neurogenesis in the dentate gyrus, which
are also linked to a high level of BDNF in the brain [
97
]. Numerous studies that have
been performed on humans and animals have confirmed that in the aging brain there is a
significant decline in BDNF and TrkB receptor expression [
98
–
100
], while spatial learning
tasks have been shown to reverse or normalize receptor levels, as seen in aged Wistar
rats [
101
]. BDNF system activation has been shown to enhance a healthy aging process,
and the administration of exogenous BDNF may be able to regenerate neurons in certain
neurodegenerative diseases [21].
4.2. The Role of BDNF and Alzheimer’s Disease
There is growing evidence of a relationship between a decreased level of BDNF ex-
pression and AD [
102
,
103
]. The pathological characterization of AD is associated with the
accumulation of
β
-amyloid peptides (A
β
) in the brain with an increased level of hyperphos-
phorylated cleaved tau microtubules [
104
]. The impaired metabolism of the
β
-amyloid
peptides results in neuritic plaque (NP) formation, where the hyperphosphorylated tau
causes neurofibrillary tangle (NFT) formation. These events result in neuronal degeneration
causing dementia [
105
]. Several studies have provided evidence that BDNF/TrkB signaling
has an essential function in amyloid processing [
105
,
106
]. This suggests that BNDF has an
important role in LTP and dendritic development, which are crucial elements in memory
function, by supporting synaptic integrity through the modulation of the glutamate recep-
tors, AMPA, and NMDA [
107
]. In neuronal cell culture, BDNF can reduce A
β
amyloid
production [
95
], while in the absence of BDNF, it is elevated [
108
]. Studies on animal
models have shown an increased level of truncated TrkB receptors in the cortex of mice
with AD, which has further worsening effects on spatial memory; moreover, overexpressed
truncated TrkB receptors disrupted BDNF/TrkB signaling in AD [
109
]. NFT and NP accu-
mulation within the hippocampus has been shown to be associated with dysregulation of
BDNF and TrkB [
110
]. The BDNF Val66Met polymorphism has been found to be associated
with profound memory decline, particularly in the preclinical phase of the disease [
111
].
According to the above observations, BDNF has protective effects against AD [112]. Thus,
studies on AD models suggest the delivery of the BDNF gene as a possible therapeutic
option for individuals with AD [
113
]. Additionally, Wang et al. identified the link between
exercise and BDNF levels as a therapeutic method for patients with AD; it was shown

Biomedicines 2022,10, 1143 8 of 18
that exercise induces the expression of BDNF, especially within the hippocampus, which
facilitates memory and cognitive function [
114
]. Table 1summarizes some research that
has addressed the relation between BDNF and AD.
Table 1. Levels and effects of BDNF in Alzheimer’s disease.
Study Objective Sample Origin BDNF Status Assay Used Conclusion Ref.
To determine the stage in which
BDNF reduced
Postmortem
cortex Declined Western plot The early stages were associated
with decreased BDNF. [103]
A meta-analysis to examine
serum BDNF in patients with
AD and mild cognitive
impairment (MCI) compared to
healthy controls
Peripheral serum
of BDNF Declined NA
A systematic review and
meta-analysis, comprising 15
studies, suggested that a
significant decline in peripheral
BDNF can only be detected in the
late stages of Alzheimer’s disease.
[82]
To explain the selective
vulnerability of certain neurons
to AD
Postmortem
cortex Decreased Western plot
Reduced BDNF may have a role in
the selectivity in neuronal
degeneration in AD
[115]
To confirm the relation between
decreased BDNF and AD
development
Postmortem
cortex
Low BDNF
mRNA RT-PCR
A decrease in brain-derived
neurotrophic factor synthesis could
significantly affect hippocampal,
cortical, and basal forebrain
cholinergic neurons and may
account for their selective
vulnerability in
Alzheimer’s disease.
[116]
Investigate plasma proteomic
markers in early-onset versus
late-onset AD
Plasma BDNF Elevated
Ultra-sensitive
immuno-based
assay
BDNF levels were elevated in both
early-onset and late-onset AD [117]
Examination of BDNF serum
level in elderly people Serum samples No significant
change ELISA
There was no association between
gender, depression, and dementia
on serum level of BDNF.
[118]
To assess BDNF serum and CSF
concentrations in 30 patients at
different stages of AD
Serum, CSF
Early stages
increased
BDNF serum,
decreased level
in late stage
ELISA
BDNF can be a good determinant
in the assessment of the
progression of AD.
[119]
4.3. The Role of BDNF in Parkinson’s Disease
PD is a neurodegenerative disease with motor and non-motor manifestation. The main
pathology is the degeneration of dopaminergic neurons in the substantia nigra (SN) [
120
].
Studies have suggested that high expression of BDNF in the SN can maintain the survival
and differentiation of the dopaminergic neurons [
121
]. Studies on PD animal models
showed that infusion of BDNF can recover the destruction of dopaminergic neurons and
D3 receptors [
121
,
122
]. The knockout mice did not experience BDNF reduction in the
dopaminergic neurons and the D3 receptor [
121
]. BDNF had a protective effect on hip-
pocampus neurons from oxidative damage that resulted from injury or inflammation that
resulted from the induction of heme oxygenase; the protective mechanism was modulated
via RAS-MAPK and the P13K-AKT signals, which induced Nrf2 nuclear translocation [
123
].
Endoplasmic reticulum (ER) stress can induce apoptosis of dopaminergic neurons causing
PD [
124
]. ER stress caused apoptosis by glycogen synthase kinase 3
β
(GSK3) activation,
cyclin D1 suppression, and AKT inactivation. TrkB overexpression stopped these mecha-
nisms via activation of the AKT signal pathway, causing overexpression of cyclin D1 and
enhancing the phosphorylation of GSK3, with the net effect of preventing apoptosis of
neuronal cells [
125
]. Furthermore,
α
-Synuclein (
α
-syn) mutations were associated with
reduced TrkB and BDNF [
126
,
127
]. Some studies have found that BDNF/Trkb axonal
signaling transport was significantly reduced in axons with an
α
-syn aggregate [
128
].
α
-syn
can interact with the TrkB receptor, specifically the kinase domain; this interaction induces
its ubiquitination, reducing TrkB expression [
129
], as shown in Figure 2. The presence of

Biomedicines 2022,10, 1143 9 of 18
BDNF can inhibit this interaction, thus blocking the destruction of it [
130
]. One recent
study has linked the BDNF genotype and response to long-term pharmacological therapy
in Parkinson’s disease patients, suggesting a role of BDNF in prediction and counseling
in the treatment of Parkinson’s disease [
131
]. Further studies should be implemented to
assess the possible therapeutic effect of BDNF in PD (Table 2).
Biomedicines 2022, 10, x FOR PEER REVIEW 9 of 18
[120]. Studies have suggested that high expression of BDNF in the SN can maintain the
survival and differentiation of the dopaminergic neurons [121]. Studies on PD animal
models showed that infusion of BDNF can recover the destruction of dopaminergic neu-
rons and D3 receptors [121,122]. The knockout mice did not experience BDNF reduction
in the dopaminergic neurons and the D3 receptor [121]. BDNF had a protective effect on
hippocampus neurons from oxidative damage that resulted from injury or inflammation
that resulted from the induction of heme oxygenase; the protective mechanism was mod-
ulated via RAS-MAPK and the P13K-AKT signals, which induced Nrf2 nuclear transloca-
tion [123]. Endoplasmic reticulum (ER) stress can induce apoptosis of dopaminergic neu-
rons causing PD [124]. ER stress caused apoptosis by glycogen synthase kinase 3β (GSK3)
activation, cyclin D1 suppression, and AKT inactivation. TrkB overexpression stopped
these mechanisms via activation of the AKT signal pathway, causing overexpression of
cyclin D1 and enhancing the phosphorylation of GSK3, with the net effect of preventing
apoptosis of neuronal cells [125]. Furthermore, α-Synuclein (α-syn) mutations were asso-
ciated with reduced TrkB and BDNF [126,127]. Some studies have found that BDNF/Trkb
axonal signaling transport was significantly reduced in axons with an α-syn aggregate
[128]. α-syn can interact with the TrkB receptor, specifically the kinase domain; this inter-
action induces its ubiquitination, reducing TrkB expression [129], as shown in Figure 2.
The presence of BDNF can inhibit this interaction, thus blocking the destruction of it [130].
One recent study has linked the BDNF genotype and response to long-term pharmacolog-
ical therapy in Parkinson’s disease patients, suggesting a role of BDNF in prediction and
counseling in the treatment of Parkinson’s disease [131]. Further studies should be imple-
mented to assess the possible therapeutic effect of BDNF in PD (Table 2).
Figure 2. This figure is adapted after modification from open access [132]. The figure shows that ER
stress will induce neuronal apoptosis by suppression of cyclin D1, activation of GSK3, and inhibition
of Akt signaling from the BDNF/TrkB. A syn aggregation can decrease the expression of the TrkB
receptor which will further result in loss of neurons.
Figure 2.
This figure is adapted after modification from open access [
132
]. The figure shows that ER
stress will induce neuronal apoptosis by suppression of cyclin D1, activation of GSK3, and inhibition
of Akt signaling from the BDNF/TrkB. A syn aggregation can decrease the expression of the TrkB
receptor which will further result in loss of neurons.
Table 2. Levels and effects of BDNF in Parkinson’s disease.
Study Objective Sample Origin BDNF Status Assay Used Conclusion Ref.
Investigating the effects of BDNF
as a neuroprotective factor and as
an adjunct therapy in PD
NA Decreased NA
In animal PD models, physical
activity increased the levels of BDNF
and TrkB, which acted as a
neuroprotective factor and resulted
in symptomatic improvement
[133]
Evaluate salivary cortisol and
plasma BDNF levels in PD
patients compared to healthy
controls
Plasma BDNF
No significant
difference in
BDNF, but
higher cortisol
in PD
ELISA
PD patients were in the early stage of
the disease, so BDNF is not a suitable
biomarker for early cases of PD
[134]
Assess the association between
neurotrophic changes and the
clinical staging and motor severity
of PD
Peripheral
BDNF Decreased ELISA
A larger decrease in BDNF (and other
immune markers) were associated
with a higher severity of PD
[135]
Evaluate the levels of serum
BDNF in recently diagnosed and
untreated PD patients
Serum BDNF Decreased Sandwich ELISA
Serum BDNF levels were lower in
recently diagnosed and untreated PD
patients compared to
healthy controls
[136]

Biomedicines 2022,10, 1143 10 of 18
Table 2. Cont.
Study Objective Sample Origin BDNF Status Assay Used Conclusion Ref.
To compare BDNF levels in PD,
essential tremor (ET), and healthy
controls
Peripheral
blood
lymphocytes
Decreased in
PD Western blot
BDNF levels were decreased in PD
patients, but no significant difference
in ET patients
[137]
Investigate the neuroprotective
role of BDNF in PD mice NA NA NA
Elevating BDNF levels reduced
mitochondrial impairment via
increasing electron transport chain
(ETC) activity and alleviating
dopaminergic loss in PD mice
[138]
4.4. Potential Biological Impact of BDNF Markers
According to a study undertaken by Weinstein et al. relating to the connection between
the level of BDNF in the serum and the risk for developing dementia, a ten-year follow up
of the effects of BDNF in a particular community showed that, out of 2131 participants,
140 participants had a positive risk of dementia and 117 of them were at positive risk of
Alzheimer’s disease [
125
]. Another study found that control participants with higher serum
BDNF levels were at minimum risk of developing dementia and AD. Interestingly, this vital
relationship of serum BDNF with threat of incidental dementia and AD was restricted to
women, participants aged >80 years, and those with a college degree [
125
]. Further studies
suggested that older women were at the highest risk of AD, as they have low serum BDNF,
which plays a role in AD growth. Serum BDNF might also operate like a new interpreter in
healthy adults [125].
Enzyme-linked immunosorbent assay kits are also known as BDNF antibody [
139
] of
pro-BDNF, which was recognized by Weinstein et al. After use of these kits, there was ease
in detecting BDNF forms in humans; it was reported that after using the kits much higher
levels of pro-BDNF and mature BDNF were observed in the serum [139].
In a cohort study, given the higher levels of both forms in human serum plus a
presumed divergent purpose, it is necessary to measure the individual serum level of both
forms (pro-BDNF and mature BDNF) in a technical way [
140
]. In addition, precautionary
drugs, mainly 7,8-dihydroxyflavone (active TrkB), are being used for dementia. These
therapeutic drugs enhance recorded low serum BDNF in healthy individuals, and for
people who later are likely to developing dementia or AD [
140
]. The main factors affecting
the circulation of BDNF levels in the body are caloric constraints and other physical
activities. BDNF acts as an intermediate among the observed links between the threat of
dementia and lifestyle [
141
]. Tracking of original and young applicants was maintained
from the year 1992 and the year 1998 for almost ten years in the Framingham study. The
study applied Cox models to relate the threat of dementia and AD with levels of BDNF
adjusting for probable or potential confounders [125].
BDNF is one of the main modulators of AD risk. Ecological features associated
with variation in BDNF brain levels, such as physical activities, might generate neuronal
vulnerability and affect risk of AD [
114
]. Trials (excluding trials on humans) involving
the release of BDNF to the brain is a dynamic and new area in translational research for
AD. A further study revealed that risk of AD is connected with BDNF blood levels [
125
].
This study encouraged FHS researchers to explore in more detail the detailed association
between BDNF in serum with the threat of dementia and AD [125].
The conclusion reported by Weinstein et al., 2014, in JAMA Neurology was that there
was an association between risk of dementia, serum BDNF, and AD in non-demented people
who were followed up for up to 10 years [
125
]. Higher BDNF levels were most frequently
related to lesser risk of the disease. Analysis by subgroup suggested the association was
restricted mainly to college-going people, women, and in the age group of people over
80 years. Increasing serum BDNF levels led to fewer consequences when account was
made for homocysteine levels and other substantial activities affecting AD risk.

Biomedicines 2022,10, 1143 11 of 18
The suggestions provided by these perplexing associations are not satisfying and
are not easily understood; a more detailed explanation regarding these crucial findings
should be less complicated and easier to understand. Certainly, ten years after diagno-
sis for dementia, levels of serum BDNF were found that were initially observed at the
treatment stages of Alzheimer’s disease. The symptoms are expressed in terms of slight
transformations in primitive functions and biased concerns. Thus, the FHS data showed
that BDNF levels act as remedial indicators, highlighting the connection of sequential
neurobiology rather than risk modulation of AD with BDNF. Increasingly, work has been
conducted to study the BDNF genes and the active process of BDNF delivery to the brain;
moreover, detailed studies regarding physical exercise and its involvement in BDNF have
been pursued. The risks of reducing homocysteine or inflammation (Lyketsoset al., 2007)
were shown to be modulated by the number of therapeutic trials by introducing a blood
indicator (collected from the periphery) of AD risk; although the results computed were
unsatisfactory. Work on the measurement of BDNF should be sustained as there is strong
evidence of its significance.
The study results regarding BDNF levels are quite interesting, but the explanation for
these is complex due to various concerns. The main question studied was the connection
of serum BDNF with brain levels. Levels of BDNF are affected by additional factors that
are considered to influence AD risk, such as physical activity [
142
] and caloric restriction.
Serum BDNF is a relative meandering pointer of these ecological issues rather than a direct
modulator of risk. The data collected indicates that the role of BDNF is not clearcut in
the mechanism of AD but shows that serum BDNF is strongly associated, being more
reactive in the case of dementia. Consideration of peripheral BDNF as a working indicator
for the measurement of the effects of remedial interventions is quite premature, and
additional studies are necessary to determine the therapeutic and diagnostic importance of
the data [143].
One recent meta-analysis study has reported a correlation of BDNF levels with acute
stroke; it was concluded that the level of serum BDNF is significantly lower in stroke
patients compared to controls. At the same time, there was no correlation between BDNF
level and the degree of the infarct or the outcome for the patient [144].
5. Recent Advancements and Challenges
The main challenge in the use of BDNF as a therapeutic intervention in neurological
disorders is its ability to reach the CNS in the desired concentration to elicit a therapeutic
response [145].
BDNF is a polar protein that is moderate in size; according to these characteristics, it
will not cross the blood-brain barrier when administered peripherally. Therefore, it needs
to be administered directly into the brain [1].
The administration of BDNF in the ventricles of the brain or intrathecally into the
CSF does not result in sufficient penetration to the brain parenchyma [
146
]. However, the
concentration of BDNF is improved when the BDNF is conjugated to polyethylene glycol
(‘pegylation’) as shown in rats, even though this may not produce a sufficient concentration
to be suitable for treatment in humans [147].
Moreover, BDNF administration is associated with side-effects with long-term use
that cannot be tolerated, including weight loss, dysesthesia, and Schwan cell migration into
the subpial space; these side effects result from the penetration of BDNF to the superficial
layers [
148
]. Ideally, BDNF should be administered in a system where it could achieve
enough therapeutic concentration in degenerated neurons with limited distribution to other
neurons to decrease the side-effects. In addition, the concentration should be maintained
for a sufficient time [
145
]. There are several methods that could be used to enable BDNF as
a therapy. These include the following:
BDNF protein infusion which involves the direct intraparenchymal administration
of BDNF [
149
,
150
]. Several clinical trials performed on Parkinson’s disease involved
use of implanted devices to infuse BDNF, with high flow rates needed to achieve the

Biomedicines 2022,10, 1143 12 of 18
desired concentration in the putamen. The method was associated with tissue damage,
as evidenced by MRI. At the same time, the lower rates were not sufficient to elicit a
therapeutic response [
150
,
151
]. Another observation was that the flowback of the protein
in the needle resulted in distribution of the BDNF into the CSF, which caused neuronal
death, as shown in animal studies. Therefore, this method needs further improvement to
be suitable, such as using an infusion system that can stop the reflux of the protein and a
catheter that can distribute the BDNF uniformly into the desired brain regions [152].
The gene delivery method is thought to be a safe and effective way to deliver BDNF
into the desired tissue and to decrease the spread to other tissues [
153
]. This method has
been tested in the treatment of Alzheimer’s disease, using adenovirus as a viral vector to
deliver BDNF gene into the nucleus basalis [
153
]. It has also been tested in the treatment of
Parkinson’s disease [154].
Other methods include the use of compounds that can stimulate the synthesis and
secretion of BDNF [
155
]. Moreover, a different approach has been proposed via the en-
hancement of Trkb receptor activation by agonists such as 7,8-dihydroxyflavone [
156
], a
compound that mimics BDNF such as LMA22A-4 [
157
], transactivation of Trkb, and, finally,
use of facilitators of receptor effects, such as adenosine A2A receptor agonists [
158
], bearing
in mind that the effectiveness of these methods could be altered by the receptor endocytosis
effect [159].
6. Conclusions
BDNF is one of the neurotrophic factors that modulate its function through the TrkB
receptor. It plays an important role in the central nervous system by the formation and
maintenance of a healthy neuronal environment most prominently reflected in cognitive
and memory function. Decreased activity of BDNF has been associated with the aging
process and with neurodegenerative disorders. The role of BDNF in treatment and as a
biomarker for diseases should be investigated thoroughly in future research.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest, financial or otherwise.
References
1.
Acheson, A.; Conover, J.C.; Fandl, J.P.; DeChiara, T.M.; Russell, M.; Thadani, A.; Squinto, S.P.; Yancopoulos, G.D.; Lindsay, R.M. A
BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 1995,374, 450–453. [CrossRef] [PubMed]
2.
Huang, E.J.; Reichardt, L.F. Trk receptors: Roles in neuronal signal transduction. Annu. Rev. Biochem.
2003
,72, 609–642. [CrossRef]
[PubMed]
3.
Maisonpierre, P.C.; Le Beau, M.M.; Espinosa, R., III; Ip, N.Y.; Belluscio, L.; Suzanne, M.; Squinto, S.; Furth, M.E.; Yancopoulos,
G.D. Human and rat brain-derived neurotrophic factor and neurotrophin-3: Gene structures, distributions, and chromosomal
localizations. Genomics 1991,10, 558–568. [CrossRef]
4.
Zigova, T.; Pencea, V.; Wiegand, S.J.; Luskin, M.B. Intraventricular Administration of BDNF Increases the Number of Newly
Generated Neurons in the Adult Olfactory Bulb. Mol. Cell. Neurosci. 1998,11, 234–245. [CrossRef]
5.
Scalzo, P.; Kümmer, A.; Bretas, T.L.; Cardoso, F.; Teixeira, A.L. Serum levels of brain-derived neurotrophic factor correlate with
motor impairment in Parkinson’s disease. J. Neurol. 2010,257, 540–545. [CrossRef]
6.
Sohrabji, F.; Lewis, D.K. Estrogen–BDNF interactions: Implications for neurodegenerative diseases. Front. Neuroendocrinol.
2006
,
27, 404–414. [CrossRef]
7.
Mughal, M.R.; Baharani, A.; Chigurupati, S.; Son, T.G.; Chen, E.; Yang, P.; Okun, E.; Arumugam, T.; Chan, S.L.; Mattson, M.P.
Electroconvulsive shock ameliorates disease processes and extends survival in huntingtin mutant mice. Hum. Mol. Genet.
2011
,
20, 659–669. [CrossRef]
8.
Monteleone, P.; Serritella, C.; Martiadis, V.; Maj, M. Decreased levels of serum brain-derived neurotrophic factor in both depressed
and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disord.
2008
,10,
95–100. [CrossRef]
9.
Gravesteijn, E. Effects of nutritional interventions on BDNF concentrations in humans: A systematic review. Nutr. Neurosci.
2021
,
56, 3295–3312. [CrossRef]
10.
Lima Giacobbo, B.; Doorduin, J.; Klein, H.C.; Dierckx, R.A.J.O.; Bromberg, E.; de Vries, E.F.J. Brain-Derived Neurotrophic Factor
in Brain Disorders: Focus on Neuroinflammation. Mol. Neurobiol. 2019,56, 3295–3312. [CrossRef]

Biomedicines 2022,10, 1143 13 of 18
11.
Whiteford, H.A.; Degenhardt, L.; Rehm, J.; Baxter, A.J.; Ferrari, A.J.; Erskine, H.E.; Charlson, F.J.; Norman, R.E.; Flaxman, A.D.;
Johns, N.; et al. Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of
Disease Study 2010. Lancet 2013,382, 1575–1586. [CrossRef]
12.
Lupien, S.J.; McEwen, B.S.; Gunnar, M.R.; Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition.
Nat. Rev. Neurosci. 2009,10, 434–445. [CrossRef] [PubMed]
13.
McEachan, R.; Taylor, N.; Harrison, R.; Lawton, R.; Gardner, P.; Conner, M. Meta-Analysis of the Reasoned Action Approach
(RAA) to Understanding Health Behaviors. Ann. Behav. Med. 2016,50, 592–612. [CrossRef] [PubMed]
14.
Perry, V.H.; Teeling, J. Microglia and macrophages of the central nervous system: The contribution of microglia priming and
systemic inflammation to chronic neurodegeneration. Semin. Immunopathol. 2013,35, 601–612. [CrossRef] [PubMed]
15.
Hyman, C.; Hofer, M.; Barde, Y.A.; Juhasz, M.; Yancopoulos, G.D.; Squinto, S.P.; Lindsay, R.M. BDNF is a neurotrophic factor for
dopaminergic neurons of the substantia nigra. Nature 1991,350, 230–232. [CrossRef] [PubMed]
16.
Pruunsild, P.; Kazantseva, A.; Aid, T.; Palm, K.; Timmusk, T. Dissecting the human BDNF locus: Bidirectional transcription,
complex splicing, and multiple promoters. Genomics 2007,90, 397–406. [CrossRef]
17.
Aid, T.; Kazantseva, A.; Piirsoo, M.; Palm, K.; Timmusk, T. Mouse and rat BDNF gene structure and expression revisited. J.
Neurosci. Res. 2007,85, 525–535. [CrossRef]
18.
Timmusk, T.; Palm, K.; Metsis, M.; Reintam, T.; Paalme, V.; Saarma, M.; Persson, H. Multiple promoters direct tissue-specific
expression of the rat BDNF gene. Neuron 1993,10, 475–489. [CrossRef]
19.
Lauterborn, J.C.; Rivera, S.; Stinis, C.T.; Hayes, V.Y.; Isackson, P.J.; Gall, C.M. Differential Effects of Protein Synthesis Inhibition on
the Activity-Dependent Expression of BDNF Transcripts: Evidence for Immediate-Early Gene Responses from Specific Promoters.
J. Neurosci. 1996,16, 7428–7436. [CrossRef]
20.
Keifer, J. Comparative Genomics of the BDNF Gene, Non-Canonical Modes of Transcriptional Regulation, and Neurological
Disease. Mol. Neurobiol. 2021,58, 2851–2861. [CrossRef]
21.
Tapia-Arancibia, L.; Aliaga, E.; Silhol, M.; Arancibia, S. New insights into brain BDNF function in normal aging and Alzheimer
disease. Brain Res. Rev. 2008,59, 201–220. [CrossRef] [PubMed]
22.
Camuso, S. Pleiotropic effects of BDNF on the cerebellum and hippocampus: Implications for neurodevelopmental disorders.
Neurobiol. Dis. 2022,163, 105606. [CrossRef] [PubMed]
23.
Miranda, M. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front.
Cell. Neurosci. 2019,13, 363. [CrossRef] [PubMed]
24.
Cattaneo, A.; Cattane, N.; Begni, V.; Pariante, C.M.; Riva, M.A. The human BDNF gene: Peripheral gene expression and protein
levels as biomarkers for psychiatric disorders. Transl. Psychiatry 2016,6, e958. [CrossRef]
25.
Kraemer, B.R.; Yoon, S.O.; Carter, B.D. The Biological Functions and Signaling Mechanisms of the p75 Neurotrophin Receptor. In
Neurotrophic Factors; Lewin, G.R., Carter, B.D., Eds.; Handbook of Experimental Pharmacology; Springer: Berlin/Heidelberg,
Germany, 2014; pp. 121–164. [CrossRef]
26.
Barkat, M.A. Nanopaclitaxel therapy: An evidence based review on the battle for next-generation formulation challenges.
Nanomedicine 2019,14, 1323–1341.
27. Minichiello, L. TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 2009,10, 850–860. [CrossRef]
28.
Matsumoto, T.; Rauskolb, S.; Polack, M.; Klose, J.; Kolbeck, R.; Korte, M.; Barde, Y.A. Biosynthesis and processing of endogenous
BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat. Neurosci. 2008,11, 131–133. [CrossRef]
29.
Bekinschtein, P.; Cammarota, M.; Igaz, L.M.; Bevilaqua, L.R.; Izquierdo, I.; Medina, J.H. Persistence of long-term memory storage
requires a late protein synthesis-and BDNF-dependent phase in the hippocampus. Neuron 2007,53, 261–277. [CrossRef]
30.
Park, H.; Poo, M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci.
2013
,14, 7–23.
[CrossRef]
31.
Castrén, E.; Kojima, M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol. Dis.
2017
,
97, 119–126. [CrossRef]
32.
Kolbeck, R.; Jungbluth, S.; Barde, Y.A. Characterisation of Neurotrophin Dimers and Monomers. Eur. J. Biochem.
1994
,225,
995–1003. [CrossRef] [PubMed]
33.
Egan, M.F.; Kojima, M.; Callicott, J.H.; Goldberg, T.E.; Kolachana, B.S.; Bertolino, A.; Zaitsev, E.; Gold, B.; Goldman, D.; Dean, M.;
et al. The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal
Function. Cell 2003,112, 257–269. [CrossRef]
34.
Chen, Z.Y.; Jing, D.; Bath, K.G.; Ieraci, A.; Khan, T.; Siao, C.J.; Herrera, D.G.; Toth, M.; Yang, C.; McEwen, B.S.; et al. Genetic
Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior. Science 2006,314, 140–143. [CrossRef] [PubMed]
35.
Ninan, I.; Bath, K.G.; Dagar, K.; Perez-Castro, R.; Plummer, M.R.; Lee, F.S.; Chao, M.V. The BDNF Val66Met Polymorphism
Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Hippocampus. J. Neurosci. 2010,30, 8866–8870. [CrossRef]
36.
Mizui, T.; Ishikawa, Y.; Kumanogoh, H.; Lume, M.; Matsumoto, T.; Hara, T.; Yamawaki, S.; Takahashi, M.; Shiosaka, S.; Itami, C.;
et al. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc.
Natl. Acad. Sci. USA 2015,112, E3067–E3074. [CrossRef]
37.
Akaneya, Y.; Tsumoto, T.; Kinoshita, S.; Hatanaka, H. Brain-Derived Neurotrophic Factor Enhances Long-Term Potentiation in
Rat Visual Cortex. J. Neurosci. 1997,17, 6707–6716. [CrossRef]

Biomedicines 2022,10, 1143 14 of 18
38. Kang, H.; Schuman, E.M. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus.
Science 1995,267, 1658–1662. [CrossRef]
39.
Kang, H.; Welcher, A.A.; Shelton, D.; Schuman, E.M. Neurotrophins and Time: Different Roles for TrkB Signaling in Hippocampal
Long-Term Potentiation. Neuron 1997,19, 653–664. [CrossRef]
40.
Patapoutian, A.; Reichardt, L.F. Trk receptors: Mediators of neurotrophin action. Curr. Opin. Neurobiol.
2001
,11, 272–280.
[CrossRef]
41.
Roback, J.D.; Marsh, H.N.; Downen, M.; Palfrey, H.C.; Wainer, B.H. BDNF-activated Sianal Transduction in Rat Cortical Glial
Cells. Eur. J. Neurosci. 1995,7, 849–862. [CrossRef]
42.
Fang, H.; Chartier, J.; Sodja, C.; Desbois, A.; Ribecco-Lutkiewicz, M.; Walker, P.R.; Sikorska, M. Transcriptional activation of the
human brain-derived neurotrophic factor gene promoter III by dopamine signaling in NT2/N neurons. J. Biol. Chem.
2003
,278,
26401–26409. [CrossRef] [PubMed]
43.
Kaplan, D.R.; Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol.
2000
,10, 381–391.
[CrossRef]
44.
Podyma, B. Metabolic homeostasis via BDNF and its receptors. Trends Endocrinol. Metab.
2021
,32, 488–499. [CrossRef] [PubMed]
45.
Roux, P.P.; Barker, P.A. Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol.
2002
,67, 203–233.
[CrossRef]
46.
Barnabé-Heider, F.; Miller, F.D. Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors
via distinct signaling pathways. J. Neurosci. 2003,23, 5149–5160. [CrossRef] [PubMed]
47.
Mattson, M.P.; Maudsley, S.; Martin, B. BDNF and 5-HT: A dynamic duo in age-related neuronal plasticity and neurodegenerative
disorders. Trends Neurosci. 2004,27, 589–594. [CrossRef]
48.
Rhee, S.G.; Bae, Y.S. Regulation of Phosphoinositide-specific Phospholipase C Isozymes. J. Biol. Chem.
1997
,272, 15045–15048.
[CrossRef]
49.
Pezet, S.; Malcangio, M.; McMahon, S.B. BDNF: A neuromodulator in nociceptive pathways? Brain Res. Rev.
2002
,40, 240–249.
[CrossRef]
50.
Brunet, A.; Bonni, A.; Zigmond, M.J.; Lin, M.Z.; Juo, P.; Hu, L.S.; Anderson, M.J.; Arden, K.C.; Blenis, J.; Greenberg, M.E. Akt
promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999,96, 857–868. [CrossRef]
51.
Hansen, H.H.; Briem, T.; Dzietko, M.; Sifringer, M.; Voss, A.; Rzeski, W.; Zdzisinska, B.; Thor, F.; Heumann, R.; Stepulak, A.; et al.
Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain. Neurobiol. Dis.
2004,16, 440–453. [CrossRef]
52.
Yuan, M. Recognition of the SARS-CoV-2 receptor binding domain by neutralizing antibodies. Biochem. Biophys. Res. Commun.
2021,538, 192–203. [CrossRef] [PubMed]
53.
Vaillant, A.R.; Mazzoni, I.; Tudan, C.; Boudreau, M.; Kaplan, D.R.; Miller, F.D. Depolarization and Neurotrophins Converge on
the Phosphatidylinositol 3-Kinase–Akt Pathway to Synergistically Regulate Neuronal Survival. J. Cell Biol.
1999
,146, 955–966.
[CrossRef] [PubMed]
54.
Almeida, R.D.; Manadas, B.J.; Melo, C.V.; Gomes, J.R.; Mendes, C.S.; Grãos, M.M.; Carvalho, R.F.; Carvalho, A.P.; Duarte, C.B.
Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell
Death Differ. 2005,12, 1329–1343. [CrossRef] [PubMed]
55.
Zhao, M.Z. Promotion on NLRC5 upregulating MHC-I expression by IFN-
γ
in MHC-I–deficient breast cancer cells. Immunol. Res.
2019,67, 497–504. [CrossRef]
56.
Emamian, E.S.; Hall, D.; Birnbaum, M.J.; Karayiorgou, M.; Gogos, J.A. Convergent evidence for impaired AKT1-GSK3
β
signaling
in schizophrenia. Nat. Genet. 2004,36, 131–137. [CrossRef]
57.
Corbit, K.C.; Foster, D.A.; Rosner, M.R. Protein kinase C
δ
mediates neurogenic but not mitogenic activation of mitogen-activated
protein kinase in neuronal cells. Mol. Cell. Biol. 1999,19, 4209–4218. [CrossRef]
58.
Barde, Y.A.; Edgar, D.; Thoenen, H. Purification of a new neurotrophic factor from mammalian brain. EMBO J.
1982
,1, 549–553.
[CrossRef]
59.
Dimitropoulou, A.; Bixby, J.L. Regulation of retinal neurite growth by alterations in MAPK/ERK kinase (MEK) activity. Brain Res.
2000,858, 205–214. [CrossRef]
60.
Cohen, S.; Levi-Montalcini, R.; Hamburger, V. A Nerve Growth-Stimulating Factor Isolated from Sarcomas 87 and 180. In The
Saga of the Nerve Growth Factor: Preliminary Studies, Discovery, Further Development; World Scientific: Singapore, 1997; pp. 156–160.
61.
Soppet, D.; Escandon, E.; Maragos, J.; Middlemas, D.S.; Raid, S.W.; Blair, J.; Burton, L.E.; Stanton, B.R.; Kaplan, D.R.; Hunter, T.;
et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase
receptor. Cell 1991,65, 895–903. [CrossRef]
62.
Ebadi, M.; Bashir, R.M.; Heidrick, M.L.; Hamada, F.M.; El Refaey, E.; Hamed, A.; Helal, G.; Baxi, M.D.; Cerutis, D.R.; Lassi, N.K.
Neurotrophins and their receptors in nerve injury and repair. Neurochem. Int. 1997,30, 347–374. [CrossRef]
63.
Eggert, S. Brothers in arms: proBDNF/BDNF and sAPP
α
/A
β
-signaling and their common interplay with ADAM10, TrkB,
p75NTR, sortilin, and sorLA in the progression of Alzheimer’s disease. Biol. Chem. 2022,403, 43–71. [CrossRef] [PubMed]
64.
Sendtner, M.; Holtmann, B.; Kolbeck, R.; Thoenen, H.; Barde, Y.A. Brain-derived neurotrophic factor prevents the death of
motoneurons in newborn rats after nerve section. Nature 1992,360, 757–759. [CrossRef] [PubMed]

Biomedicines 2022,10, 1143 15 of 18
65.
Lindsay, J.; Laurin, D.; Verreault, R.; Hébert, R.; Helliwell, B.; Hill, G.B.; McDowell, I. Risk Factors for Alzheimer’s Disease: A
Prospective Analysis from the Canadian Study of Health and Aging. Am. J. Epidemiol. 2002,156, 445–453. [CrossRef] [PubMed]
66.
Nikoletopoulou, V.; Lickert, H.; Frade, J.M.; Rencurel, C.; Giallonardo, P.; Zhang, L.; Bibel, M.; Barde, Y.A. Neurotrophin receptors
TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 2010,467, 59–63. [CrossRef] [PubMed]
67.
Pintilie, S.R. Neuroprotective effects of physical exercise: Implications in health and disease. Rev. Med. Rom.
2021
,68, 383–389.
[CrossRef]
68.
Pang, P.T.; Teng, H.K.; Zaitsev, E.; Woo, N.T.; Sakata, K.; Zhen, S.; Teng, K.K.; Yung, W.H.; Hempstead, B.L.; Lu, B. Cleavage of
proBDNF by tPA/Plasmin Is Essential for Long-Term Hippocampal Plasticity. Science 2004,306, 487–491. [CrossRef]
69.
Bamji, S.X.; Rico, B.; Kimes, N.; Reichardt, L.F. BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting
cadherin–β-catenin interactions. J. Cell Biol. 2006,174, 289–299. [CrossRef]
70.
Lu, B.; Chow, A. Neurotrophins and hippocampal synaptic transmission and plasticity. J. Neurosci. Res.
1999
,58, 76–87. [CrossRef]
71.
Li, Y.; Yui, D.; Luikart, B.W.; McKay, R.M.; Li, Y.; Rubenstein, J.L.; Parada, L.F. Conditional ablation of brain-derived neurotrophic
factor-TrkB signaling impairs striatal neuron development. Proc. Natl. Acad. Sci. USA 2012,109, 15491–15496. [CrossRef]
72.
Gauthier, L.R.; Charrin, B.C.; Borrell-Pagès, M.; Dompierre, J.P.; Rangone, H.; Cordelières, F.P.; De Mey, J.; MacDonald, M.E.;
Leßmann, V.; Humbert, S.; et al. Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF
Vesicular Transport along Microtubules. Cell 2004,118, 127–138. [CrossRef]
73.
Yamamoto, H.; Gurney, M.E. Human platelets contain brain-derived neurotrophic factor. J. Neurosci.
1990
,10, 3469–3478.
[CrossRef] [PubMed]
74.
Sarchielli, P.; Greco, L.; Stipa, A.; Floridi, A.; Gallai, V. Brain-derived neurotrophic factor in patients with multiple sclerosis. J.
Neuroimmunol. 2002,132, 180–188. [CrossRef]
75.
Neves-Pereira, M.; Cheung, J.K.; Pasdar, A.; Zhang, F.; Breen, G.; Yates, P.; Sinclair, M.; Crombie, C.; Walker, N.; St Clair, D.M.
BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol. Psychiatry 2005,10, 208–212. [CrossRef] [PubMed]
76.
Neves-Pereira, M.; Mundo, E.; Muglia, P.; King, N.; Macciardi, F.; Kennedy, J.L. The Brain-Derived Neurotrophic Factor Gene
Confers Susceptibility to Bipolar Disorder: Evidence from a Family-Based Association Study. Am. J. Hum. Genet.
2002
,71, 651–655.
[CrossRef]
77.
Tacke, C.D.A.J. Role of a Novel TrkB Agonist Antibody in Positively Modulating the Architecture and Synaptic Plasticity of
Hippocampal Neurons in Health and Disease. 2021. Available online: https://publikationsserver.tu-braunschweig.de/receive/
dbbs_mods_00069356 (accessed on 1 January 2020).
78.
Katoh-Semba, R.; Takeuchi, I.K.; Semba, R.; Kato, K. Distribution of Brain-Derived Neurotrophic Factor in Rats and Its Changes
with Development in the Brain. J. Neurochem. 1997,69, 34–42. [CrossRef]
79.
Araki, T. The effects of microglia- and astrocyte-derived factors on neurogenesis in health and disease. Eur. J. Neurosci.
2021
,54,
5880–5901. [CrossRef]
80.
Eide, F.F.; Vining, E.R.; Eide, B.L.; Zang, K.; Wang, X.Y.; Reichardt, L.F. Naturally Occurring Truncated trkB Receptors Have
Dominant Inhibitory Effects on Brain-Derived Neurotrophic Factor Signaling. J. Neurosci. 1996,16, 3123–3129. [CrossRef]
81. Schinder, A.F.; Poo, M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 2000,23, 639–645. [CrossRef]
82.
Ng, T.K.S.; Ho, C.S.H.; Tam, W.W.S.; Kua, E.H.; Ho, R.C.M. Decreased Serum Brain-Derived Neurotrophic Factor (BDNF) Levels
in Patients with Alzheimer’s Disease (AD): A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2019,20, 257. [CrossRef]
83.
Hayek, L.E.; Khalifeh, M.; Zibara, V.; Assaad, R.A.; Emmanuel, N.; Karnib, N.; El-Ghandour, R.; Nasrallah, P.; Bilen, M.; Ibrahim,
P.; et al. Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal
Brain-Derived Neurotrophic Factor (BDNF). J. Neurosci. 2019,39, 2369–2382.
84.
Cirulli, F.; Berry, A.; Chiarotti, F.; Alleva, E. Intrahippocampal administration of BDNF in adult rats affects short-term behavioral
plasticity in the Morris water maze and performance in the elevated plus-maze. Hippocampus
2004
,14, 802–807. [CrossRef]
[PubMed]
85.
Bolton, M.M.; Pittman, A.J.; Lo, D.C. Brain-Derived Neurotrophic Factor Differentially Regulates Excitatory and Inhibitory
Synaptic Transmission in Hippocampal Cultures. J. Neurosci. 2000,20, 3221–3232. [CrossRef] [PubMed]
86.
Schaaf, M.J.M.; Workel, J.O.; Lesscher, H.M.; Vreugdenhil, E.; Oitzl, M.S.; Ron de Kloet, E. Correlation between hippocampal
BDNF mRNA expression and memory performance in senescent rats. Brain Res. 2001,915, 227–233. [CrossRef]
87.
Guerra-Crespo, M.; Ubieta, R.; Joseph-Bravo, P.; Charli, J.L.; Pérez-Martínez, L. BDNF increases the early expression of TRH
mRNA in fetal TrkB+ hypothalamic neurons in primary culture. Eur. J. Neurosci. 2001,14, 483–494. [CrossRef]
88.
Marmigère, F.; Choby, C.; Rage, F.; Richard, S.; Tapia-Arancibia, L. Rapid Stimulatory Effects of Brain-Derived Neurotrophic
Factor and Neurotrophin-3 on Somatostatin Release and Intracellular Calcium Rise in Primary Hypothalamic Cell Cultures.
Neuroendocrinology 2001,74, 43–54. [CrossRef]
89.
Givalois, L.; Arancibia, S.; Alonso, G.; Tapia-Arancibia, L. Expression of Brain-Derived Neurotrophic Factor and Its Receptors in
the Median Eminence Cells with Sensitivity to Stress. Endocrinology 2004,145, 4737–4747. [CrossRef]
90.
Crook, T.; Bartus, R.T.; Ferris, S.H.; Whitehouse, P.; Cohen, G.D.; Gershon, S. Age-associated memory impairment: Proposed
diagnostic criteria and measures of clinical change—Report of a national institute of mental health work group. Dev. Neuropsychol.
1986,2, 261–276. [CrossRef]
91. Hebb, D.O. The Organization of Behavior: A Neuropsychological Theory; Psychology Press: London, UK, 2005; 379p.

Biomedicines 2022,10, 1143 16 of 18
92.
Thoenen, H. Neurotrophins and activity-dependent plasticity. In Progress in Brain Research; Neural Plasticity and Regeneration;
Elsevier: Amsterdam, The Netherlands, 2000; Volume 128, pp. 183–191. Available online: http://www.sciencedirect.com/
science/article/pii/S0079612300280163 (accessed on 12 January 2021).
93. Burke, S.N.; Barnes, C.A. Neural plasticity in the ageing brain. Nat. Rev. Neurosci. 2006,7, 30–40. [CrossRef]
94.
Barnes, C.A. Normal aging: Regionally specific changes in hippocampal synaptic transmission. Trends Neurosci.
1994
,17, 13–18.
[CrossRef]
95.
Gooney, M.; Messaoudi, E.; Maher, F.O.; Bramham, C.R.; Lynch, M.A. BDNF-induced LTP in dentate gyrus is impaired with age:
Analysis of changes in cell signaling events. Neurobiol. Aging 2004,25, 1323–1331. [CrossRef]
96.
Rex, C.S.; Lauterborn, J.C.; Lin, C.Y.; Kramár, E.A.; Rogers, G.A.; Gall, C.M.; Lynch, G. Restoration of Long-Term Potentiation in
Middle-Aged Hippocampus After Induction of Brain-Derived Neurotrophic Factor. J. Neurophysiol.
2006
,96, 677–685. [CrossRef]
[PubMed]
97.
Granger, R.; Deadwyler, S.; Davis, M.; Moskovitz, B.; Kessler, M.; Rogers, G.; Lynch, G. Facilitation of glutamate receptors reverses
an age-associated memory impairment in rats. Synapse 1996,22, 332–337. [CrossRef]
98.
Hattiangady, B.; Rao, M.S.; Shetty, G.A.; Shetty, A.K. Brain-derived neurotrophic factor, phosphorylated cyclic AMP response
element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of
the hippocampus. Exp. Neurol. 2005,195, 353–371. [CrossRef] [PubMed]
99.
Lommatzsch, M.; Zingler, D.; Schuhbaeck, K.; Schloetcke, K.; Zingler, C.; Schuff-Werner, P.; Virchow, J.C. The impact of age,
weight and gender on BDNF levels in human platelets and plasma. Neurobiol. Aging 2005,26, 115–123. [CrossRef] [PubMed]
100.
Mora, F.; Segovia, G.; del Arco, A. Aging, plasticity and environmental enrichment: Structural changes and neurotransmitter
dynamics in several areas of the brain. Brain Res. Rev. 2007,55, 78–88. [CrossRef] [PubMed]
101.
Silhol, M.; Arancibia, S.; Maurice, T.; Tapia-Arancibia, L. Spatial memory training modifies the expression of brain-derived
neurotrophic factor tyrosine kinase receptors in young and aged rats. Neuroscience 2007,146, 962–973. [CrossRef] [PubMed]
102.
Ferrer, I.; Marín, C.; Rey, M.J.; Ribalta, T.; Goutan, E.; Blanco, R.; Tolosa, E.; Martí, E. BDNF and Full-length and Truncated TrkB
Expression in Alzheimer Disease. Implications in Therapeutic Strategies. J. Neuropathol. Exp. Neurol.
1999
,58, 729–739. [CrossRef]
103.
Peng, S.; Garzon, D.J.; Marchese, M.; Klein, W.; Ginsberg, S.D.; Francis, B.M.; Mount, H.T.; Mufson, E.J.; Salehi, A.; Fahnestock,
M. Decreased Brain-Derived Neurotrophic Factor Depends on Amyloid Aggregation State in Transgenic Mouse Models of
Alzheimer’s Disease. J. Neurosci. 2009,29, 9321–9329. [CrossRef]
104. Selkoe, D.J. Amyloid β-Protein and the Genetics of Alzheimer’s Disease. J. Biol. Chem. 1996,271, 18295–18298. [CrossRef]
105.
Wang, Z.H.; Xiang, J.; Liu, X.; Yu, S.P.; Manfredsson, F.P.; Sandoval, I.M.; Wu, S.; Wang, J.Z.; Ye, K. Deficiency in BDNF/TrkB
Neurotrophic Activity Stimulates
δ
-Secretase by Upregulating C/EBP
β
in Alzheimer’s Disease. Cell Rep.
2019
,28, 655–669.e5.
[CrossRef]
106.
Rohe, M.; Synowitz, M.; Glass, R.; Paul, S.M.; Nykjaer, A.; Willnow, T.E. Brain-Derived Neurotrophic Factor Reduces Amyloido-
genic Processing through Control of SORLA Gene Expression. J. Neurosci. 2009,29, 15472–15478. [CrossRef] [PubMed]
107.
Banerjee, M. Emphasizing roles of BDNF promoters and inducers in Alzheimer’s disease for improving impaired cognition and
memory. J. Basic Clin. Physiol. Pharmacol. 2022. [CrossRef]
108.
Matrone, C.; Ciotti, M.T.; Mercanti, D.; Marolda, R.; Calissano, P. NGF and BDNF signaling control amyloidogenic route and A
β
production in hippocampal neurons. Proc. Natl. Acad. Sci. USA 2008,105, 13139–13144. [CrossRef] [PubMed]
109.
Numakawa, T.; Odaka, H. Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer’s Disease: Beneficial
Effects of Flavonoids for Neuroprotection. Int. J. Mol. Sci. 2021,22, 5719. [CrossRef] [PubMed]
110.
Ginsberg, S.D.; Malek-Ahmadi, M.H.; Alldred, M.J.; Chen, Y.; Chen, K.; Chao, M.V.; Counts, S.E.; Mufson, E.J. Brain-derived
neurotrophic factor (BDNF) and TrkB hippocampal gene expression are putative predictors of neuritic plaque and neurofibrillary
tangle pathology. Neurobiol. Dis. 2019,132, 104540. [CrossRef]
111.
Lim, Y.Y. BDNF VAL66MET polymorphism and memory decline across the spectrum of Alzheimer’s disease. Genes Brain Behav.
2021,20, e12724. [CrossRef]
112.
Kitiyanant, N.; Kitiyanant, Y.; Svendsen, C.N.; Thangnipon, W. BDNF-, IGF-1- and GDNF-Secreting Human Neural Progenitor
Cells Rescue Amyloid β-Induced Toxicity in Cultured Rat Septal Neurons. Neurochem. Res. 2012,37, 143–152. [CrossRef]
113.
Arancibia, S.; Silhol, M.; Moulière, F.; Meffre, J.; Höllinger, I.; Maurice, T.; Tapia-Arancibia, L. Protective effect of BDNF against
beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol. Dis. 2008,31, 316–326. [CrossRef]
114.
Wang, R.; Holsinger, R.M.D. Exercise-induced brain-derived neurotrophic factor expression: Therapeutic implications for
Alzheimer’s dementia. Ageing Res. Rev. 2018,48, 109–121. [CrossRef]
115.
Michalski, B.; Fahnestock, M. Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Mol.
Brain Res. 2003,111, 148–154. [CrossRef]
116.
Holsinger, R.M.D.; Schnarr, J.; Henry, P.; Castelo, V.T.; Fahnestock, M. Quantitation of BDNF mRNA in human parietal cortex by
competitive reverse transcription-polymerase chain reaction: Decreased levels in Alzheimer’s disease. Mol. Brain Res.
2000
,76,
347–354. [CrossRef]
117.
Elahi, F.M.; Casaletto, K.B.; La Joie, R.; Walters, S.M.; Harvey, D.; Wolf, A.; Edwards, L.; Rivera-Contreras, W.; Karydas, A.; Cobigo,
Y.; et al. Plasma Biomarkers of Astrocytic and Neuronal Dysfunction in Early- and Late-Onset Alzheimer’s Disease. Alzheimers
Dement. 24 December 2019. Available online: https://www.sciencedirect.com/science/article/pii/S1552526019353737 (accessed
on 28 March 2022).

Biomedicines 2022,10, 1143 17 of 18
118.
Ziegenhorn, A.A.; Schulte-Herbrüggen, O.; Danker-Hopfe, H.; Malbranc, M.; Hartung, H.D.; Anders, D.; Lang, U.E.; Steinhagen-
Thiessen, E.; Schaub, R.T.; Hellweg, R. Serum neurotrophins—A study on the time course and influencing factors in a large old
age sample. Neurobiol. Aging 2007,28, 1436–1445. [CrossRef] [PubMed]
119.
Laske, C.; Stransky, E.; Leyhe, T.; Eschweiler, G.W.; Wittorf, A.; Richartz, E.; Bartels, M.; Buchkremer, G.; Schott, K. Stage-
dependent BDNF serum concentrations in Alzheimer’s disease. J. Neural Transm. 2006,113, 1217–1224. [CrossRef] [PubMed]
120.
Elkouzi, A.; Vedam-Mai, V.; Eisinger, R.S.; Okun, M.S. Emerging therapies in Parkinson disease—Repurposed drugs and new
approaches. Nat. Rev. Neurol. 2019,15, 204–223. [CrossRef] [PubMed]
121.
Parain, K.; Murer, M.G.; Yan, Q.; Faucheux, B.; Agid, Y.; Hirsch, E.; Raisman-Vozari, R. Reduced expression of brain-derived
neurotrophic factor protein in Parkinson’s disease substantia nigra. Neuroreport 1999,10, 557–561. [CrossRef] [PubMed]
122.
Huang, Y. Serum concentration and clinical significance of brain-derived neurotrophic factor in patients with Parkinson’s disease
or essential tremor. J. Int. Med. Res. 2018,46, 1477–1485. [CrossRef]
123.
Bruna, B.; Lobos, P.; Herrera-Molina, R.; Hidalgo, C.; Paula-Lima, A.; Adasme, T. The signaling pathways underlying BDNF-
induced Nrf2 hippocampal nuclear translocation involve, R.O.S.; RyR-Mediated Ca
2+
signals, ERK and PI3K. Biochem. Biophys.
Res. Commun. 2018,505, 201–207. [CrossRef]
124.
Ryu, E.J.; Harding, H.P.; Angelastro, J.M.; Vitolo, O.V.; Ron, D.; Greene, L.A. Endoplasmic Reticulum Stress and the Unfolded
Protein Response in Cellular Models of Parkinson’s Disease. J. Neurosci. 2002,22, 10690–10698. [CrossRef]
125.
Weinstein, G.; Beiser, A.S.; Choi, S.H.; Preis, S.R.; Chen, T.C.; Vorgas, D.; Au, R.; Pikula, A.; Wolf, P.A.; DeStefano, A.L.; et al.
Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia: The Framingham Heart Study. JAMA Neurol.
2014
,71,
55–61. [CrossRef]
126.
Lotharius, J.; Brundin, P. Pathogenesis of parkinson’s disease: Dopamine, vesicles and
α
-synuclein. Nat. Rev. Neurosci.
2002
,3,
932–942. [CrossRef]
127.
Miller, K.M. Synucleinopathy-associated pathogenesis in Parkinson’s disease and the potential for brain-derived neurotrophic
factor. NPJ Park. Dis. 2021,7, 1–9. [CrossRef] [PubMed]
128.
Kohno, R.; Sawada, H.; Kawamoto, Y.; Uemura, K.; Shibasaki, H.; Shimohama, S. BDNF is induced by wild-type
α
-synuclein but
not by the two mutants, A30P or A53T, in glioma cell line. Biochem. Biophys. Res. Commun. 2004,318, 113–118. [CrossRef]
129.
Volpicelli-Daley, L.A.; Gamble, K.L.; Schultheiss, C.E.; Riddle, D.M.; West, A.B.; Lee, V.M.Y. Formation of
α
-synuclein Lewy
neurite–like aggregates in axons impedes the transport of distinct endosomes. Mol. Biol. Cell
2014
,25, 4010–4023. [CrossRef]
[PubMed]
130.
Kang, S.S.; Zhang, Z.; Liu, X.; Manfredsson, F.P.; Benskey, M.J.; Cao, X.; Xu, J.; Sun, Y.E.; Ye, K. TrkB neurotrophic activities
are blocked by
α
-synuclein, triggering dopaminergic cell death in Parkinson’s disease. Proc. Natl. Acad. Sci. USA
2017
,114,
10773–10778. [CrossRef]
131.
Sortwell, C.E. BDNF rs6265 Genotype Influences Outcomes of Pharmacotherapy and Subthalamic Nucleus Deep Brain Stimulation
in Parkinson’s Disease. Neuromodul. Malden Mass. 2021. [CrossRef] [PubMed]
132.
Jin, W. Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson’s Disease. J. Clin. Med.
2020
,9, 257.
[CrossRef] [PubMed]
133.
Palasz, E.; Wysocka, A.; Gasiorowska, A.; Chalimoniuk, M.; Niewiadomski, W.; Niewiadomska, G. BDNF as a Promising
Therapeutic Agent in Parkinson’s Disease. Int. J. Mol. Sci. 2020,21, 1170. [CrossRef]
134.
Costa, C.M.; de Oliveira, G.L.; Fonseca, A.C.S.; de Lana, R.C.; Polese, J.C.; Pernambuco, A.P. Levels of cortisol and neurotrophic
factor brain-derived in Parkinson’s disease. Neurosci. Lett. 2019,708, 134359. [CrossRef]
135.
Roy, A.; Mondal, B.; Banerjee, R.; Choudhury, S.; Chatterjee, K.; Dey, S.; Kumar, H. Do peripheral immune and neurotrophic
markers correlate with motor severity of Parkinson’s disease? J. Neuroimmunol. 2021,354, 577545. [CrossRef]
136.
Hernández-Vara, J.; Sáez-Francàs, N.; Lorenzo-Bosquet, C.; Corominas-Roso, M.; Cuberas-Borròs, G.; Lucas-Del Pozo, S.; Carter,
S.; Armengol-Bellapart, M.; Castell-Conesa, J. BDNF levels and nigrostriatal degeneration in “drug naïve” Parkinson’s disease
patients. An “in vivo” study using I-123-FP-CIT SPECT. Parkinsonism Relat. Disord. 2020,78, 31–35. [CrossRef]
137.
Huang, Y.; Huang, C.; Yun, W. Peripheral BDNF/TrkB protein expression is decreased in Parkinson’s disease but not in Essential
tremor. J. Clin. Neurosci. 2019,63, 176–181. [CrossRef] [PubMed]
138.
Chang, E.; Wang, J. Brain-derived neurotrophic factor attenuates cognitive impairment and motor deficits in a mouse model of
Parkinson’s disease. Brain Behav. 2021,11, e2251. [CrossRef]
139.
Yoshida, T.; Ishikawa, M.; Iyo, M.; Hashimoto, K. Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF) and Its
Precursor proBDNF in Healthy Subjects. Open Clin. Chem. J.
2012
,5. Available online: https://benthamopen.com/ABSTRACT/
TOCCHEMJ-5-7 (accessed on 7 January 2021). [CrossRef]
140.
Hashimoto, K. Sigma-1 receptor chaperone and brain-derived neurotrophic factor: Emerging links between cardiovascular
disease and depression. Prog. Neurobiol. 2013,100, 15–29. [CrossRef] [PubMed]
141.
Erickson, K.I.; Miller, D.L.; Roecklein, K.A. The Aging Hippocampus: Interactions between Exercise, Depression, and BDNF.
Neuroscientist 2012,18, 82–97. [CrossRef] [PubMed]
142.
Oliff, H.S.; Berchtold, N.C.; Isackson, P.; Cotman, C.W. Exercise-induced regulation of brain-derived neurotrophic factor (BDNF)
transcripts in the rat hippocampus. Mol. Brain Res. 1998,61, 147–153. [CrossRef]
143.
Mori, Y. Serum BDNF as a Potential Biomarker of Alzheimer ’s Disease: Verification Through Assessment of Serum, Cerebrospinal
Fluid, and Medial Temporal Lobe Atrophy. Front. Neurol. 2021,12, 511. [CrossRef]

Biomedicines 2022,10, 1143 18 of 18
144. Karantali, E. Serum BDNF Levels in Acute Stroke: A Systematic Review and Meta-Analysis. Medicina 2021,57, 297. [CrossRef]
145.
Nagahara, A.H.; Tuszynski, M.H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat. Rev. Drug
Discov. 2011,10, 209–219. [CrossRef]
146.
Kells, A.P.; Henry, R.A.; Connor, B. AAV–BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor
function impairment. Gene Ther. 2008,15, 966–977. [CrossRef]
147.
Ankeny, D.P.; McTigue, D.M.; Guan, Z.; Yan, Q.; Kinstler, O.; Stokes, B.T.; Jakeman, L.B. Pegylated Brain-Derived Neurotrophic
Factor Shows Improved Distribution into the Spinal Cord and Stimulates Locomotor Activity and Morphological Changes after
Injury. Exp. Neurol. 2001,170, 85–100. [CrossRef] [PubMed]
148.
Winkler, J.; Ramirez, G.A.; Kuhn, H.G.; Peterson, D.A.; Day-Lollini, P.A.; Stewart, G.R.; Tuszynski, M.H.; Gage, F.H.; Thal, L.J.
Reversible schwann cell hyperplasia and sprouting of sensory and sympathetic neurites after intraventricular administration of
nerve growth factor. Ann. Neurol. 1997,41, 82–93. [CrossRef] [PubMed]
149.
Mucke, L.; Masliah, E.; Yu, G.Q.; Mallory, M.; Rockenstein, E.M.; Tatsuno, G.; Hu, K.; Kholodenko, D.; Johnson-Wood, K.;
McConlogue, L. High-Level Neuronal Expression of A
β
1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice:
Synaptotoxicity without Plaque Formation. J. Neurosci. 2000,20, 4050–4058. [CrossRef] [PubMed]
150.
Nutt, J.G.; Burchiel, K.J.; Comella, C.L.; Jankovic, J.; Lang, A.E.; Laws, E.R.; Lozano, A.M.; Penn, R.D.; Simpson, R.K.; Stacy,
M.; et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology
2003
,60, 69–73.
[CrossRef] [PubMed]
151.
Lang, A.E.; Gill, S.; Patel, N.K.; Lozano, A.; Nutt, J.G.; Penn, R.; Brooks, D.J.; Hotton, G.; Moro, E.; Heywood, P.; et al. Randomized
controlled trial of intraputamenal glial cell line–derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol.
2006
,59,
459–466. [CrossRef]
152.
Hovland, D.N.; Boyd, R.B.; Butt, M.T.; Engelhardt, J.A.; Moxness, M.S.; Ma, M.H.; Emery, M.G.; Ernst, N.B.; Reed, R.P.; Zeller,
J.R.; et al. Reprint: Six-Month Continuous Intraputamenal Infusion Toxicity Study of Recombinant Methionyl Human Glial Cell
Line-Derived Neurotrophic Factor (r-metHuGDNF) in Rhesus Monkeys. Toxicol. Pathol. 2007,35, 1013–1029. [CrossRef]
153.
Gasmi, M.; Herzog, C.D.; Brandon, E.P.; Cunningham, J.J.; Ramirez, G.A.; Ketchum, E.T.; Bartus, R.T. Striatal Delivery of
Neurturin by CERE-120, an AAV2 Vector for the Treatment of Dopaminergic Neuron Degeneration in Parkinson’s Disease. Mol.
Ther. 2007,15, 62–68. [CrossRef]
154.
Herzog, C.D.; Brown, L.; Gammon, D.; Kruegel, B.; Lin, R.; Wilson, A.; Bolton, A.; Printz, M.; Gasmi, M.; Bishop, K.M.; et al.
Expression, bioactivity, and safety 1 year after adeno-associated viral vector type 2–mediated delivery of neurturin to the monkey
nigrostriatal system support cere-120 for parkinson’s disease. Neurosurgery 2009,64, 602–613. [CrossRef]
155.
Fukuchi, M.; Okuno, Y.; Nakayama, H.; Nakano, A.; Mori, H.; Mitazaki, S.; Nakano, Y.; Toume, K.; Jo, M.; Takasaki, I.; et al.
Screening inducers of neuronal BDNF gene transcription using primary cortical cell cultures from BDNF-luciferase transgenic
mice. Sci. Rep. 2019,9, 11833. [CrossRef]
156.
Jang, S.W.; Liu, X.; Yepes, M.; Shepherd, K.R.; Miller, G.W.; Liu, Y.; Wilson, W.D.; Xiao, G.; Blanchi, B.; Sun, Y.E.; et al. A selective
TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc. Natl. Acad. Sci. USA
2010
,107, 2687–2692.
[CrossRef]
157.
Simmons, D.A.; Belichenko, N.P.; Yang, T.; Condon, C.; Monbureau, M.; Shamloo, M.; Jing, D.; Massa, S.M.; Longo, F.M. A Small
Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington’s
Disease. J. Neurosci. 2013,33, 18712–18727. [CrossRef] [PubMed]
158.
Diógenes, M.J.; Costenla, A.R.; Lopes, L.V.; Jerónimo-Santos, A.; Sousa, V.C.; Fontinha, B.M.; Ribeiro, J.A.; Sebastiao, A.M.
Enhancement of LTP in Aged Rats is Dependent on Endogenous BDNF. Neuropsychopharmacology
2011
,36, 1823–1836. [CrossRef]
[PubMed]
159.
Grimes, M.L.; Zhou, J.; Beattie, E.C.; Yuen, E.C.; Hall, D.E.; Valletta, J.S.; Topp, K.S.; LaVail, J.H.; Bunnett, N.W.; Mobley, W.C.
Endocytosis of Activated TrkA: Evidence that Nerve Growth Factor Induces Formation of Signaling Endosomes. J. Neurosci.
1996
,
16, 7950–7964. [CrossRef] [PubMed]