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All content in this area was uploaded by Alfredo Sanabria-Castro on Mar 08, 2018
Content may be subject to copyright.
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Review
Ann Neurosci 2017;24:46–54
DOI: 10.1159/000464422
Molecular Pathogenesis of
Alzheimer’s Disease: An Update
Alfredo Sanabria-Castro Ileana Alvarado-Echeverría Cecilia Monge-Bonilla
Research Unit, Hospital San Juan de Dios, Costa Rican Social Security Fund (CCSS), San José , Costa Rica
Search Strategy and Selection Criteria
A literature review was conducted in January 2016 us-
ing PubMed, Ovid, and Science Direct with the following
descriptors: Alzheimer’s disease (AD), neurobiology, pa-
thology, review. Results obtained ranged between 150
and 2,200 records after the combination of different key-
words. Scientific publications between 1996 and 2015
either in English or Spanish, discussing the neuromolecu-
lar hypotheses of AD were selected. Papers concerning
clinical presentation, diagnostic methods, and treatment
were excluded.
Alzheimer’s disease (AD) was first described in 1906
at a conference in Tubingen, Germany by Alois Alzheimer
[1] , as a “peculiar severe disease process of the cerebral
cortex.” In recent times, AD is considered a chronic or
progressive syndrome, characterized by impaired cogni-
tive capacity beyond what could be considered a conse-
quence of normal aging; that affects the memory, think-
ing, orientation, comprehension, learning, language, and
judgment. More than one hundred years have passed
since the first pathophysiological aspects of AD were de-
scribed. Neurobiological mechanisms underlying AD
have been a key element in the understanding of the pa-
thology, currently the most important alterations identi-
Keywords
Alzheimer’s disease · Dementia · Amyloid · Neurobiology ·
Pathogenesis · Review
Abstract
Dementia is a chronic or progressive syndrome, character-
ized by impaired cognitive capacity beyond what could be
considered a consequence of normal aging. It affects the
memory, thinking process, orientation, comprehension, cal-
culation, learning ability, language, and judgment; although
awareness is usually unaffected. Alzheimer’s disease (AD) is
the most common form of dementia; symptoms include
memory loss, difficulty solving problems, disorientation in
time and space, among others. The disease was first de-
scribed in 1906 at a conference in Tubingen, Germany by
Alois Alzheimer. One hundred and ten years since its first
documentation, many aspects of the pathophysiology of AD
have been discovered and understood, however gaps of
knowledge continue to exist. This literature review summa-
rizes the main underlying neurobiological mechanisms in
AD, including the theory with emphasis on amyloid peptide,
cholinergic hypothesis, glutamatergic neurotransmission,
the role of tau protein, and the involvement of oxidative
stress and calcium. © 2017 S. Karger AG, Basel
Received: July 16, 2016
Accepted: July 26, 2016
Published online: April 21, 2017
Alfredo Sanabria-Castro
Research Unit, Hospital San Juan de Dios
Costa Rican Social Security Fund (CCSS)
Paseo Colón, Streets 14–20 San José 10103 (Costa Rica)
E-Mail asccheo @ yahoo.com
© 2017 S. Karger AG, Basel
www.karger.com/aon
Molecular Pathogenesis of AD:
An Update
Ann Neurosci 2017;24:46–54
DOI: 10.1159/000464422
47
fied can be explained through: the amyloid peptide theo-
ry, the cholinergic hypothesis that includes glutamatergic
neurotransmission alterations, the role of tau protein,
and the involvement of oxidative stress (OS) and calcium.
The Cholinergic Hypothesis
At a molecular level, the cholinergic hypothesis is the
first and most studied approach that describes AD patho-
physiology. It was defined more than 30 years ago as a
primary degenerative process capable of selectively dam-
aging groups of cholinergic neurons in the hippocampus,
frontal cortex, amygdala, nucleus basalis, and medial sep-
tum, regions and structures that serve important func-
tional roles in conscious awareness, attention, learning,
memory, and other mnemonic processes
[2] . This selec-
tive alteration generates a downregulation of cholinergic
markers such as acetyltransferase and acetylcholinester-
ase that associate with the onset of cognitive impairment
[3, 4] ; through the existence of proportionality between
the decrease in cholinergic markers, the density of neuro-
fibrillary alterations, and the severity of the pathology.
The main findings supporting this premise are the fact
that non-selective muscarinic antagonists such as sco-
polamine-induced cognitive impairment, favor the pro-
duction of beta-amyloid peptide and decrease the activ-
ity of α-secretase
[5] . Some triterpenoid saponins have
shown to reduce scopolamine-induced amnesia
[6–8]
and non-selective and selective muscarinic agonists have
shown to improve learning and memory. Selective M1
muscarinic agonists are a pivotal target that link major
hallmarks of AD. The exact molecular mechanisms of the
effect of cholinergic drugs in learning and memory, and
their clinical treatment viability are still being studied
[9–
12] .
This hypothesis was reinforced through immunohis-
tochemical, neuroimaging, and other analyses that re-
vealed: a decrease in the number and density of nicotinic
receptors in AD patients (mainly α4β2 subtype), a re-
duced expression of α3, α4, and α7 subunits at cortex and
hippocampus, and a decline in the binding ability of α7
hippocampal and α4 cortical receptors
[13–15] .
The main alterations in cholinergic neurons consid-
ered in this hypothesis are: choline uptake, impaired ace-
tylcholine release, deficits in the expression of nicotinic
and muscarinic receptors, dysfunctional neurotrophin
support, and deficits in axonal transport
[16–18] . Recent
studies have shown that amyloid β interacts with cholin-
ergic receptors affecting their function
[19] .
Because the cholinergic and glutamatergic systems sig-
nificantly interact during neurotransmission alterations
in the glutamatergic, signaling has been associated with
cholinergic disruptions found in AD
[20] , an aspect that
enhances cholinergic hypothesis. This postulate dictates
that acetylcholine and its receptors, especially (α7)
5 are
considered as neuroprotective by modulating glutamate-
mediated neuronal excitability
[21, 22] . In AD abnormal-
ities in glutamatergic, neurotransmission is initially ob-
served at the entorhinal cortex (EC), which is followed by
further neurotransmission defects in the hippocampus,
amygdala, frontal cortex, and parietal cortex
[23] .
The physiological glutamatergic neurotransmission in
the hippocampus produces a cytosolic calcium signal,
which mediates synaptic plasticity phenomena such as
long-term potentiation (LTP), encouraging learning and
memory consolidation
[24] . However, a sustained in-
crease in calcium, sodium, and chloride ions as a result of
the hyperactivation of NMDA glutamate receptors has
been associated with excessive depolarization of the post-
synaptic membrane, onset neurodegenerative processes
and cell death
[25–27] . Likewise, an increase in intraneu-
ronal calcium as a consequence of a dysfunctional gluta-
matergic neurotransmission can generate a long-lasting
depression in the cerebellum (LTD), with calcium over-
load in mitochondria, activation of nitric oxide synthesis,
generation of free radicals, OS, initiation apoptosis and
neuronal death
[28–31] .
Experimentally incubating neurons with glutamate
promotes the deposit of filaments similar to neurofibril-
lary tangles observed in AD. Also, the exposure of neuro-
nal cultures to amyloid β promotes glutamate-induced
neurotoxicity and regulates the expression of NMDA
receptors on the membrane
[32, 33] .
At the synaptic level, the lack of enzymes responsible
for the degradation of glutamate causes neuronal trans-
porters at the neuronal and glial levels to be responsible
for the reuptake of the excess of neurotransmitter
[34] .
In AD, the inhibition of presynaptic and glial glutamate
transport
[35] , the reduced activity of glutamine synthe-
tase (converts glutamate to glutamine)
[36] , the discrete
depolarization of neurons, and stimulation of nitric ox-
ide production by amyloid β
[23] favor the prolonged
presence of extra neuronal glutamate, and hence the
continued receptor stimulation and excitotoxicity
[16,
34] .
The cholinergic hypothesis has served as a basis for the
majority of treatment strategies and drug development
approaches (acetylcholinesterase inhibitors, cholinergic
precursors, cholinergic receptor agonists, allosteric cho-
Sanabria-Castro/Alvarado-Echeverría/
Monge-Bonilla
Ann Neurosci 2017;24:46–54
DOI: 10.1159/000464422
48
linergic receptor potentiators, NMDA receptor blockers)
for AD. Currently there is consensus that the observed
relationship between cognitive impairment and de-
creased cholinergic transmission in the brain plays an im-
portant role in AD but by itself does not establish defini-
tive causation of the disease
[37, 38] .
The Amyloid Hypothesis
In the amyloid cascade hypothesis of AD, the disease
is analyzed as a series of abnormalities in the process and
secretion of the amyloid precursor protein (APP), where
an inequality between production and clearance of amy-
loid β is the triggering event and the most important fac-
tor; responsible for other abnormalities observed in AD
[39] . Amyloid β is a peptide with high resistance to pro-
teolytic degradation. It consists of 37–43 amino acids, in
which the isoforms 1–40 and 1–42 are the most common
[40] . The 1–42 amyloid peptide isoform is the most hy-
drophobic and is considered to have the greatest toxicity
[23] . Because of its physical characteristics, it often ac-
quires the configuration of a β-pleated sheet
[41] , show-
ing a greater tendency to aggregate and form the core of
the amyloid plaque
[42–44] . It is the main component of
amyloid neuritic plaques
[43, 45] .
The processing of APP at the plasma membrane con-
stitutes the origin of the amyloid peptide ( Fig.1 ). APP is
Abnormal Normal
APPsį
APP
APPsDŽ
Oligomer
DŽƩ
Amyloid
plaque
DŽ
DŽ$5
*35
&;&5
Alterations
T phosphorilation
Calcium dysfunction
Mitochondrial
dysfunction
Synaptic alteration
Cognitive impairment
'25
$$5
P$&K5
P*OX5*, 5
+7$&
&5+5
3$&5
FGF, EGF, NGF
Cytokines
Hormones
ADAM
BACE1
C99 & AICD
AICD
YY
S
į
DŽƩ
Fig. 1. Amyloidogenic and non-amyloidogenic processing of the
APP. The top part of the figure shows the 2 main paths in the
processing of APP, the most important elements involved, and
the main alterations associated with the amyloidogenic pathway
of APP. The bottom part of the figure shows potential modula-
tors of the secretase activity (activation of receptors, growth fac-
tors, cytokines, hormones). α, α-secretase activity; β, β-secretase
activity; γ, γ-secretase activity; BACE1, β-site – APP – cleaving
enzyme 1; βA, amyloid β peptide; ADAM, α-secretase; APPsα
and APPsβ, soluble portions produced by the effect of α- and
β-secretase; C83, fragment of 83 amino acids of the carboxyl ter-
minal portion produced by the effect of α-secretase; C99, frag-
ment of 99 amino acids of the carboxyl terminal portion pro-
duced by effect of β-secretase; p3, peptide resulting from
γ-secretase; AICD, carboxy-terminal fragment referred to as the
intracellular domain of APP; T, Tau protein; mAChRs, musca-
rinic acetylcholine receptors; mGluR, metabotropic glutamate
receptors; 5HT, serotonin receptors; CRHR1, receptor 1 of the
corticotropin-releasing hormone; PAC1R, receptor 1 of pituitary
adenylate cyclase; FGF, EGF, NGF, growth factors of fibroblasts,
epidermis and the nervous system respectively; DOR, opioid
receptor δ; A2AR, adenosine receptor 2A; β2-AR, β2 adrenergic
receptor; GPR3, receptor 3 coupled to protein G; CXCR2,
chemokine receptor 2.
Molecular Pathogenesis of AD:
An Update
Ann Neurosci 2017;24:46–54
DOI: 10.1159/000464422
49
a transmembrane glycoprotein of type I and its specific
function is unclear; however it is known that its expres-
sion is increased during cellular stress phenomena. APP
processing is performed by a series of ruptures, which in-
volves an initial breakdown by enzymes with α-secretase
activity, mainly enzymes belonging to the disintegrin and
metalloprotease (ADAM) family including: ADAM10,
ADAM17, and ADAM19
[45, 46] . ADAM activity can be
modulated by different situations such as receptor activa-
tion, growth factors, cytokines, and hormones. The exci-
sion produced by α-secretase leads to the formation and
release of a peptide of the amino terminal portion called
APPs α, which is soluble under certain conditions
[47]
and a fragment of the carboxyl terminal portion (C83)
[48] . The APPsα is found in lower quantities in AD pa-
tients
[49] and has been associated with trophic and neu-
roprotective functions
[50] .
In patients with AD, the first APP rupture at an extra-
cellular level, generates a shorter soluble amino terminal
portion (APPsβ) and a longer terminal carboxyl fragment
(C99)
[51, 52] . This split is performed mainly by BACE1
(β- site – APP – cleaving enzyme), an ubiquitous trans-
membrane protease with β-secretase activity. BACE1 ex-
pression can be modulated by frequently seen situations
in neurodegenerative diseases and aging such as OS, isch-
emia, inflammation, hypoxia, and trauma
[51, 53–55] .
After γ-secretase, consisting of a heteromeric complex
of 4 subunits called: presenilins (PSEN1 and PSEN2),
nicastrin (NCSTN), APH-1, from the acronym anterior
pharynx defensive phenotype 1 (APH-1a and APH-1b)
and PEN – 2 (PS-enhancer-2)
[56] produces a cut in the
γ site releasing the carboxyl terminal fragment named
APP intracellular domain (AICD) and producing the am-
yloid β peptide, which is secreted, aggregated, and accu-
mulated in extracellular plaques due to its low solubility
( Fig.2 ) [57] . It has been observed that APH-1 inhibits the
production of amyloid β peptide while the PEN-2 favors
it
[58, 59] .
Several studies have shown the in vitro and in vivo
neurotoxicities of various forms of amyloid β
[60] ; how-
ever, the exact mechanisms are quite complex and not
fully understood
[37, 52] . So far the relation between the
specific site of action of amyloid β and its structural di-
versity is unknown; what is clear is that the amino acid
sequence that is contained between positions 25 and 35
of the primary structure has greater neurotoxicity.
Concentrations of amyloid β peptide are determined
by the balance between generation and clearance; in AD
APP
1
4
40
42
5
C31
$DŽ
Nicastrin
Y-Secretase
Oligomerization
BACE PEN-2 Presenilin
AICD
2b
2a
APH-1
Y
a
ı
3
DŽ6HFUHWDVH
Fig. 2. Production of amyloid β peptide from sequential proteolytic
breaks of the APP. The figure shows the sequence of phases in the
processing of APP in the formation of amyloid β peptide and its
oligomerization. Numbers (1, 2a, 2b, 3, 4, and 5) refer to intervention
sites where the production of amyloid β peptide could be modulated
with possible therapeutic utility. α, α-secretase cut site; γ, γ-secretase
cut site γ; ε, cut site ε of γ-secretase; BACE, β-secretase; Aβ, amyloid
β peptide; AICD, carboxy-terminal fragment referred to as APP in-
tracellular domain.
Sanabria-Castro/Alvarado-Echeverría/
Monge-Bonilla
Ann Neurosci 2017;24:46–54
DOI: 10.1159/000464422
50
patients, a clearance abnormality leads to the accumula-
tion of amyloid β in the brain
[61] . The transport of amy-
loid β through the blood-brain barrier is mediated by re-
ceptors, the passage of the peptide from the brain to the
blood occurs by interaction with LRP-1 receptors (Lipo-
protein receptor-related protein-1) and the action of p-
glycoproteins. Increased levels of amyloid β and aging,
decrease of the expression of LRP-1 receptors results in
an accumulation of amyloid peptide in the central ner-
vous system (CNS).
The transit of amyloid β peptide into the brain through
the blood-brain barrier
[62] also occurs via receptors, pri-
marily through multi-ligand AGE (advanced glycation
end products) receptors or RAGE. RAGE expression is
determined by the concentration of its own ligands. In
contrast to the expression decrease of LPR-1s due to high
levels of amyloid β in the brain, RAGE increases the ex-
pression under these conditions.
Since RAGE interaction with amyloid β causes: in-
flammatory responses at the endothelium level, endothe-
lial cell apoptosis, decreased cerebral blood flow, and
suppression of LTP; RAGE may play a role in the devel-
opment of neurovascular changes observed in AD
[62–
65] .
Proteolytic degradation of amyloid β peptide is car-
ried out mainly by neprilysin (NEP) and the insulin-
degrading enzyme (IDE). During aging and in AD pa-
tients, the expression of NEP and IDE decreases, caus-
ing an increase in the concentration of amyloid β peptide
in the brain
[61, 66] . In patients with AD, decreased
quantity and activity of NEP is seen especially in the
cortex and hippocampus, but not in other regions of the
brain.
The secretion of IDE in the brain is regulated by the
microglia, and similar to NEP its distribution and con-
centration also presents differences in AD patients. Low-
er concentrations have been identified in the cortex and
hippocampus, where the predominant form has a higher
degree of oxidation
[9] .
The endosomal lysosomal pathway is also an impor-
tant regulator of the processing of APP
[67, 68] and of
the tau protein metabolism
[69] . Because of the impor-
tance of this pathway for cellular maintenance and its
role in the immune system, recent studies suggest that
dysfunctions in neuronal autophagy causing an in-
crease in the amount and size of endosomes at the cel-
lular level, may be involved in the pathogenesis of AD
[70–74] , as these changes are seen before the appear-
ance of senile plaques and neurofibrillary tangles in the
brain
[72, 74] . Other studies report the absence of a di-
rect relationship between quantity and size of lyso-
somes and AD [75] .
The amyloid cascade hypothesis has the highest accep-
tance rate; however, current studies support the idea that
not only amyloid β but other fragments from the process-
ing of APP, such as C83 or AICD, contribute to the patho-
genesis of AD resulting in difficulty to attribute the path-
ological features of the disease exclusively to the amyloid
peptide
[60] .
The Tau (τ) Protein
The amyloid cascade hypothesis consists of the pro-
duction and accumulation of amyloid β peptide as the
beginning of the disease process; however, it does not
completely explain the etiopathogenesis of AD. In this
hypothesis, the τ protein arises as a secondary patho-
genic event that subsequently causes neurodegeneration
[76, 77] . In vitro experiments using various cell types,
ranging from neuronal cell lines to primary hippocam-
pal and cortical neurons and hippocampal organotypic
cultures, have demonstrated that amyloid β induces
τ-alterations
[78–80] . These include mainly an increased
phosphorylation and cytoplasmic and dendritic translo-
cation often linked to neurodegeneration
[81] .
The τ protein is a highly soluble protein that re-
latesto the microtubules and its function under normal
conditions consists of stabilizing them. These microtu-
bules provide support for structural changes, axonal
transport, and neuronal growth
[69, 82, 83] . In the
CNS, the τ protein presents itself in 6 different isoforms
that vary in the number of binding sites for microtu-
bules and the amount of exons they possess
[82] . In AD,
dysfunctions occur in phosphorylation processes of τ
protein, resulting in a hyperphosphorylation of the
molecule.
Hyperphosphorylated protein τ presents aberrant ag-
gregation with the cytoskeletal proteins; it shows a lower
grade of interaction with microtubules which favors an
increase of free tau protein that leads to greater aggrega-
tion and fibrillization of itself, with the consequent mal-
function of axonal transport
[84, 85] .
Scientific literature reports changes in τ protein and
amyloid β oligomers as the most important factors re-
sponsible for neuronal dysfunction in the pathogenesis of
AD
[46, 86] . Likewise neurofibrillary tangles observed
initially in the EC and hippocampus subsequently extend
to the amygdala and cortical areas (temporal, frontal, and
parietal)
[57, 85] .
Molecular Pathogenesis of AD:
An Update
Ann Neurosci 2017;24:46–54
DOI: 10.1159/000464422
51
Contribution of OS in the Pathogenesis of AD
It has been long recognized that one of the common
characteristics in neurodegenerative diseases is the rela-
tionship between OS and neuronal apoptosis
[87] . OS is
a condition in which the balance between production of
active reactive oxygen species (ROS) and the level of an-
tioxidants is significantly disturbed, resulting in cell dam-
age. ROS chemically interact with biological molecules
such as nucleic acids, proteins and lipids, and cell organ-
elles
[88] .
In addition to the established pathology of senile
plaques and neurofibrillary tangles, the presence of ex-
tensive OS is a characteristic of AD brains. The accumu-
lation of free radical damage, alterations in the activities
or expression of antioxidant enzymes such as superoxide
dismutase and catalase are also present in AD patients
[89] . Although OS is an important factor in AD patho-
genesis, the mechanisms by which the redox balance is
altered and the sources of free radicals are not exactly
known. It has been demonstrated that abnormal accumu-
lation of amyloid β is capable of promoting the formation
of ROS through a mechanism that involves the activation
of NMDA receptors
[90] , and that OS may augment am-
yloid β production and aggregation as well facilitate tau
phosphorylation and polymerization, forming a vicious
cycle that promotes the initiation and progression of AD
[91] .
Neuronal mitochondria (essential for cellular
metabolism) show metabolic abnormalities in AD
models. It has been demonstrated that mitochondria
are quite vulnerable to OS, which may directly disrupt
its functions (energy production, decrease of antioxi-
dant enzymes, and loss of membrane potential), gener-
ating a further increase in ROS levels that finally pro-
duce cell death by caspase activation and apoptosis
[92–
94] .
Calcium Homeostasis in AD
Calcium, an ubiquitous intracellular messenger, regu-
lates multiple physiological functions, generating con-
centration gradients and binding to several proteins, re-
ceptors, and ion channels. The regulation of intracellular
calcium homeostasis is a very complex mechanism that is
vital for several cellular pathways and is thus involved in
cell survival and death. Two organelles play a major role
in calcium homeostasis, the endoplasmic reticulum (ER)
and mitochondria, whereas ATPase calcium pump and
the sodium-calcium exchanger are the 2 main systems in-
volved in calcium efflux through the plasma membrane
[95, 96] . Ca 2+ is continuously exchanged between the cy-
tosol and the lumen of the ER. Overload of intracellular
calcium due to a blockage or dysfunction of the transport
system leads to the cleavage of several proteins and other
substrates, OS, perturbs energy production
[97] , stimu-
lates protein production (amyloid β and τ protein)
[98],
and induces cell death through necrosis and/or apoptosis
[99, 100] .
In AD, the ability of neurons to regulate the influx,
efflux, and subcellular compartmentalization of calcium
is compromised
[101] . These disruptions involve sev-
eral mechanisms, such as alterations of calcium buffer-
ing capacities, deregulation of calcium channel activi-
ties, excitotoxicity or disruption of mitochondrial func-
tions. Alterations resulting from calcium disruption are
the result of age-related OS, metabolic impairment in
combination with disease-related accumulation of Aβ
oligomers and the presence of mutations of genes that
encode presenilin
[102] . Particularly, Aβ may promote
cellular calcium overload by inducing membrane-asso-
ciated OS and forming pores in the membrane
[103–
105] .
Conclusion
During the last decades, advances in cellular biology
have been essential for understanding the molecular
mechanisms underlying AD. Currently it is known that
the molecular pathogenesis of AD is complex and in-
volves several theories or hypothesis where many diverse
factors interrelate. However, none of these postulates
alone is able to clarify the entire aspect regarding the pa-
thology, and further studies are required. Aspects like the
initial causes of the disease such as the abnormal forma-
tion of amyloid β, and the mechanisms by which it affects
neurons and nicotinic acetylcholine receptors and the re-
lation between the disruption of cholinergic pathways
and the cognitive deficits of AD are still not fully under-
stood.
New discoveries that contribute to the elucidation of
the molecular pathogenesis of AD and its relations are
crucial because they can allow the development of new
therapeutic strategies for the treatment of a condition
where current drug therapy lacks the ability to prevent its
occurrence and progression.
Sanabria-Castro/Alvarado-Echeverría/
Monge-Bonilla
Ann Neurosci 2017;24:46–54
DOI: 10.1159/000464422
52
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