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Fyn Kinase Activity and Its Role in Neurodegenerative Disease Pathology: a Potential Universal Target?

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Bianca Guglietti
Bianca Guglietti
Bianca Guglietti
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Srisankavi Sivasankar
Srisankavi Sivasankar
Srisankavi Sivasankar
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Sanam Mustafa at University of Adelaide
Sanam Mustafa
Frances Corrigan at University of South Australia
Frances Corrigan
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Abstract and Figures

Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Neurodegenerative diseases are amongst the leading cause of death and disability worldwide and, due to the ageing population, prevalence is predicted to rise in the coming years. Symptoms across neurodegenerative diseases are both debilitating and degenerative in nature and, concerningly, there are currently no disease-modifying therapies to prevent their progression. As such, it is important to identify potential new therapeutic targets. This review will outline the role of Fyn in normal/homeostatic processes, as well as degenerative/pathological mechanisms associated with neurodegenerative diseases, such as demyelination, pathological protein aggregation, neuroinflammation and cognitive dysfunction.
Schematic representation of Fyn. The multidomain Fyn structure extends from an N-terminus to a carboxyl (C)-terminus, with multiple domains in between the terminuses, each with its own specific functionality. The Src homology (SH) 4 (SH4) domain at the N-terminus anchors Fyn to the cell membrane [17]. The subsequent domain, referred to as the unique region, is poorly conserved amongst SFK members and thus allows for Fyn-specific functions [21, 22]. Both the SH3 domain and its neighbouring SH2 domain are capable of binding to signalling molecules within the cell. However, the SH2 domain also serves as the binding site for a phosphorylated Y531 motif when Fyn is in its inactive state. Connecting the SH2 and SH1 domains is the proline-rich linker region that can interact with the SH3 domain to form an inactive conformation during Fyn’s inactive state. The linker region is followed by the catalytic SH1 domain that is well conserved amongst all SFK members. This particular domain includes the Y420 motif; the phosphorylation of which is essential for Fyn activation. Equally important for the regulation of Fyn activation is the Y531 motif, located on the C-terminus [7, 10, 21, 23]. Figure created in BioRender.com (2021)
Schematic representation of Fyn. The multidomain Fyn structure extends from an N-terminus to a carboxyl (C)-terminus, with multiple domains in between the terminuses, each with its own specific functionality. The Src homology (SH) 4 (SH4) domain at the N-terminus anchors Fyn to the cell membrane [17]. The subsequent domain, referred to as the unique region, is poorly conserved amongst SFK members and thus allows for Fyn-specific functions [21, 22]. Both the SH3 domain and its neighbouring SH2 domain are capable of binding to signalling molecules within the cell. However, the SH2 domain also serves as the binding site for a phosphorylated Y531 motif when Fyn is in its inactive state. Connecting the SH2 and SH1 domains is the proline-rich linker region that can interact with the SH3 domain to form an inactive conformation during Fyn’s inactive state. The linker region is followed by the catalytic SH1 domain that is well conserved amongst all SFK members. This particular domain includes the Y420 motif; the phosphorylation of which is essential for Fyn activation. Equally important for the regulation of Fyn activation is the Y531 motif, located on the C-terminus [7, 10, 21, 23]. Figure created in BioRender.com (2021)
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Overview of the role of Fyn in physiological processes associated with myelination and T cell-mediated inflammation. Actin dynamics—Fyn phosphorylation increases RhoGTPase activity, downregulating RhoA and altering actin dynamics to allow hyperextension of oligodendroglial processes, enabling differentiation, maturation, and axonal contact. Microtubule assembly—Fyn tyrosines bind to tau and α-tubulin, stabilising oligodendroglial processes, orchestrating axon-glial contact, and facilitating transport of myelin towards the axon. Myelin basic protein—contactin/integrin complex activates Fyn in lipid rafts, phosphorylating the MBP mRNA QK1 protein, leading to granular dissociation and subsequent synthesis of MBP. Growth factors—BDNF phosphorylates Fyn, activating the MAPK signalling pathway and promoting myelin growth. Within T cells—Fyn is required for T cell development and subsequent differentiation of CD4 + T cells, which infiltrate the CNS and differentiate depending on APC to produce inflammatory cytokines. Figure created in BioRender.com (2021)
Overview of the role of Fyn in physiological processes associated with myelination and T cell-mediated inflammation. Actin dynamics—Fyn phosphorylation increases RhoGTPase activity, downregulating RhoA and altering actin dynamics to allow hyperextension of oligodendroglial processes, enabling differentiation, maturation, and axonal contact. Microtubule assembly—Fyn tyrosines bind to tau and α-tubulin, stabilising oligodendroglial processes, orchestrating axon-glial contact, and facilitating transport of myelin towards the axon. Myelin basic protein—contactin/integrin complex activates Fyn in lipid rafts, phosphorylating the MBP mRNA QK1 protein, leading to granular dissociation and subsequent synthesis of MBP. Growth factors—BDNF phosphorylates Fyn, activating the MAPK signalling pathway and promoting myelin growth. Within T cells—Fyn is required for T cell development and subsequent differentiation of CD4 + T cells, which infiltrate the CNS and differentiate depending on APC to produce inflammatory cytokines. Figure created in BioRender.com (2021)
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Overview of the role of Fyn in physiological and pathological processes inAlzheimer’s disease. Fyn phosphorylates the Y682 subunit of APP, promoting amyloidogenic signalling and the aggregation of Aβ. Aβ aggregates in turn phosphorylate Fyn, where, in the AD brain, Fyn phosphorylation promotes hyperphosphorylation of Tau and the formation of neurofibrillary tangles (NFTs). This process can result in further upregulation of Fyn. Aβ aggregates also bind to cellular prion receptor protein (PrPc), which phosphorylate Fyn. Collectively, in AD, increased Fyn activity results in hyperphosphorylation of the NMDAR2B subunit, leading to increased calcium influx and subsequent excitotoxity. Figure created in BioRender.com (2021)
Overview of the role of Fyn in physiological and pathological processes inAlzheimer’s disease. Fyn phosphorylates the Y682 subunit of APP, promoting amyloidogenic signalling and the aggregation of Aβ. Aβ aggregates in turn phosphorylate Fyn, where, in the AD brain, Fyn phosphorylation promotes hyperphosphorylation of Tau and the formation of neurofibrillary tangles (NFTs). This process can result in further upregulation of Fyn. Aβ aggregates also bind to cellular prion receptor protein (PrPc), which phosphorylate Fyn. Collectively, in AD, increased Fyn activity results in hyperphosphorylation of the NMDAR2B subunit, leading to increased calcium influx and subsequent excitotoxity. Figure created in BioRender.com (2021)
… 
Overview of the role of Fyn in microglia under inflammatory conditions. Initiating event (e.g. α-syn presence/pathogen) binds to a membrane receptor, leading to activation of Fyn. Fyn upregulates PKCδ activity, leading to the activation of NF-κB and causing the translocation of the p65 component into the nucleus, leading to the transcription of pro-inflammatory cytokine genes such as IL-1β (left). Simultaneously, Fyn activation also leads to the internalisation of α-syn aggregates, priming the NLRP3 inflammasome directly and indirectly (via mitochondrial and lysosomal dysfunction), leading to the activation and conversion of pro-IL-1β to IL-1β (Figure adapted from Panicker 2019). Figure created in BioRender.com (2021)
Overview of the role of Fyn in microglia under inflammatory conditions. Initiating event (e.g. α-syn presence/pathogen) binds to a membrane receptor, leading to activation of Fyn. Fyn upregulates PKCδ activity, leading to the activation of NF-κB and causing the translocation of the p65 component into the nucleus, leading to the transcription of pro-inflammatory cytokine genes such as IL-1β (left). Simultaneously, Fyn activation also leads to the internalisation of α-syn aggregates, priming the NLRP3 inflammasome directly and indirectly (via mitochondrial and lysosomal dysfunction), leading to the activation and conversion of pro-IL-1β to IL-1β (Figure adapted from Panicker 2019). Figure created in BioRender.com (2021)
… 
Overview of Fyn dysfunction in neurodegenerative diseases and potential commonalities. Multiple sclerosis—increased Fyn is implicated in the production of pro-inflammatory cytokines via T cell-mediated inflammation. Its role in the promotion of myelination is well established; however, alterations to Fyn activity in MS are currently unknown. Alzheimer’s disease—increased Fyn phosphorylation is associated with pathological Aß cleavage which hyperphosphorylate tau, leading to the formations of NFTs. Aß aggregates binds to PrPc, phosphorylating Fyn. Collectively, increased Fyn phosphorylation drives NMDA dysfunction and excitotoxicity. Parkinson’s disease—increased Fyn phosphorylation is required for the inflammatory response in PD mediated by glial cells (astrocytes and microglia). “ + ” indicates potential common pathological processes observed across diseases in which Fyn may play a role in mediating. Figure created in BioRender.com (2021)
Overview of Fyn dysfunction in neurodegenerative diseases and potential commonalities. Multiple sclerosis—increased Fyn is implicated in the production of pro-inflammatory cytokines via T cell-mediated inflammation. Its role in the promotion of myelination is well established; however, alterations to Fyn activity in MS are currently unknown. Alzheimer’s disease—increased Fyn phosphorylation is associated with pathological Aß cleavage which hyperphosphorylate tau, leading to the formations of NFTs. Aß aggregates binds to PrPc, phosphorylating Fyn. Collectively, increased Fyn phosphorylation drives NMDA dysfunction and excitotoxicity. Parkinson’s disease—increased Fyn phosphorylation is required for the inflammatory response in PD mediated by glial cells (astrocytes and microglia). “ + ” indicates potential common pathological processes observed across diseases in which Fyn may play a role in mediating. Figure created in BioRender.com (2021)
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https://doi.org/10.1007/s12035-021-02518-3
Fyn Kinase Activity andIts Role inNeurodegenerative Disease
Pathology: aPotential Universal Target?
BiancaGuglietti1· SrisankaviSivasankar1· SanamMustafa1,2· FrancesCorrigan1· LyndseyE.Collins‑Praino1,2
Received: 14 May 2021 / Accepted: 3 August 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several
integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More
recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as
multiple sclerosis (MS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Neurodegenerative diseases are amongst the
leading cause of death and disability worldwide and, due to the ageing population, prevalence is predicted to rise in the com-
ing years. Symptoms across neurodegenerative diseases are both debilitating and degenerative in nature and, concerningly,
there are currently no disease-modifying therapies to prevent their progression. As such, it is important to identify potential
new therapeutic targets. This review will outline the role of Fyn in normal/homeostatic processes, as well as degenerative/
pathological mechanisms associated with neurodegenerative diseases, such as demyelination, pathological protein aggrega-
tion, neuroinflammation and cognitive dysfunction.
Keywords Parkinson’s disease· Alzheimer’s disease· Multiple sclerosis· Therapeutic· Inflammation· NMDA receptors
Neurodegenerative diseases are amongst the leading cause
of death and disability worldwide [1]. They encompass a
range of diseases associated with progressive loss of neu-
rons, the most common of which include multiple sclerosis
(MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s dis-
ease (AD) and Parkinson’s disease (PD). Involving a range
of motor and cognitive impairments, neurodegenerative
diseases are both progressive and incapacitating in nature.
Due to increased life expectancy and population growth
worldwide, prevalence of these age-associated diseases is
expected to continue to rise [2]. Accordingly, these represent
a considerable burden on worldwide health-care systems
and the individuals and carers who experience them. For
example, for PD alone, counts of prevalence, mortality and
disability-adjusted life years (DALYs) more than doubled
from 1990 to 2016 [3]. Similarly, it currently accounts for
a total US economic burden of $52 billion, a figure that
has previously been under-estimated and that is projected to
surpass $79 billion by 2037 [4].
Perhaps the greatest concern regarding the increasing
prevalence of neurodegenerative diseases are the limitations
of current therapeutic interventions. At present, there are no
available disease-modifying agents for these conditions, with
currently available treatments largely restricted to sympto-
matic relief [5]. These do nothing to halt, delay or slow the
inevitable degenerative progression of pathologies observed,
highlighting the growing need to identify novel therapeutic
targets. A potential approach may be to target common cel-
lular mechanisms underlying several of the major neuro-
degenerative diseases. Due to its diverse role in the human
central nervous system (CNS), one such promising target
may be the tyrosine kinase Fyn.
Fyn is one of eleven members of the Src family of tyros-
ine kinases (SFKs) [6]. Widely expressed in many tissues,
in recent years, Fyn has garnered significant attention in
cancer research due to its role in the signalling pathways
that control cell proliferation, migration, invasion and
apoptosis [7]. Excitingly, invivo work demonstrated Src
family inhibitors, including Fyn, were able to inhibit solid
tumour growth [8]. Unfortunately, the progression to phase
II human trials in cancers, such as melanoma, breast cancer
* Lyndsey E. Collins-Praino
Lyndsey.collins-praino@adelaide.edu.au
1 Department ofMedical Sciences, University ofAdelaide,
SG31, Helen Mayo South, Adelaide, SA5005, Australia
2 ARC Centre ofExcellence forNanoscale BioPhotonics,
University ofAdelaide, Adelaide, Australia
/ Published online: 25 August 2021
Molecular Neurobiology (2021) 58:5986–6005
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Fyn activation is essential for the myelination of oligodendrocytes, as shown in previous studies where Fyn-deficient mice exhibited abnormal myelination (Umemori et al., 1994). An increasing number of studies have demonstrated that Fyn controls multiple signaling transduction pathways through actin dynamics, microtubule assembly, protein expression of myelin basic protein (MBP), and mitogenactivated protein (MAP) kinase during myelination, as reported previously (Guglietti et al., 2021). ...
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During myelination, large quantities of proteins are synthesized and transported from the endoplasmic reticulum (ER)‐trans‐Golgi network (TGN) to their appropriate locations within the intracellular region and/or plasma membrane. It is widely believed that oligodendrocytes uptake neuronal signals from neurons to regulate the endocytosis‐ and exocytosis‐mediated intracellular trafficking of major myelin proteins such as myelin‐associated glycoprotein (MAG) and proteolipid protein 1 (PLP1). The small GTPases of the adenosine diphosphate (ADP) ribosylation factor (Arf) family constitute a large group of signal transduction molecules that act as regulators for intracellular signaling, vesicle sorting, or membrane trafficking in cells. Studies on mice deficient in Schwann cell–specific Arfs‐related genes have revealed abnormal myelination formation in peripheral nerves, indicating that Arfs‐mediated signaling transduction is required for myelination in Schwann cells. However, the complex roles in these events remain poorly understood. This review aims to provide an update on signal transduction, focusing on Arf and its activator ArfGEF (guanine nucleotide exchange factor for Arf) in oligodendrocytes and Schwann cells. Future studies are expected to provide important information regarding the cellular and physiological processes underlying the myelination of oligodendrocytes and Schwann cells and their function in modulating neural activity. image
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... Galanin was downregulated in our COVID-19 patients and operates on the neuroendocrine axis with various functions throughout the central and peripheral nervous and endocrine systems [113]. Fyn, elevated in our COVID-19 cohort, has a harmful role in neurological diseases and may be a potential target for neurodegenerative disease due to its ß-amyloid signalling and tau interactions [114][115][116]. ...
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... This led to the identi cation of ten core targets: MAPK1, APP, FYN, GSK3B, TGFB1, PTGS2, NFKB1, EGFR, SRC, and AKT1 (Fig. 2c). KEGG pathway and Gene Ontology function analyses con rmed that these core targets play major roles in the biochemical pathways and processes of neurodegeneration, cancer, kinase activities, in ammatory responses, and apoptotic processes (Demuro et al., 2021;Guglietti et al., 2021;Zou et al., 2023), thus validating their activity in neuroin ammation (Fig. 4). ...
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... Moreover, the mACh-SFK coupling in the hippocampus and striatum is thought to be critical for maintaining normal memory, cognitive behavior, mood, and movement. Dysfunction of this coupling is linked to pathogenesis of various neuropsychiatric and neurological illnesses (Ge et al., 2020;Guglietti et al., 2021;Rajani et al., 2021;Portugal et al., 2022;Wang et al., 2022). ...
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Fyn Knock-Down Prevents Levodopa-Induced Dyskinesia in a Mouse Model of Parkinson’s Disease
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Full-text available
  • Jun 2021
Dopamine replacement by levodopa is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as levodopa-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor antagonist amantadine, which has limited efficacy. The NMDA receptor is indeed the most plausible target to manage LID in PD and recently the kinase Fyn- one of its key regulators- became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intra-striatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with levodopa. The miRNA-Fyn was delivered either before or after levodopa exposure to assess its ability to prevent or revert dyskinesia. Pre-administration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-ΔFosB protein levels –a marker of LID– as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggesting that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA silencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.
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Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy
Article
Full-text available
  • Jun 2021
  • NEUROBIOL DIS
We have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyrosine kinase inhibitor, saracatinib (SAR, also known as AZD0530), in the rat kainate (KA) model of TLE. SAR treatment for a week, starting the first dose (25 mg/kg, oral) 4 h after the onset of SE, significantly reduced spontaneously recurring seizures and epileptiform spikes during the four months of continuous video-EEG monitoring. Immunohistochemistry of brain sections and Western blot analyses of hippocampal lysates at 8-day (8d) and 4-month post-SE revealed a significant reduction of SE-induced astrogliosis, microgliosis, neurodegeneration, phosphorylated Fyn/Src-419 and PKCδ-tyr311, in SAR-treated group when compared with the vehicle control. We also found the suppression of nitroxidative stress markers such as iNOS, 3-NT, 4-HNE, and gp91phox in the hippocampus, and nitrite and ROS levels in the serum of the SAR-treated group at 8d post-SE. The qRT-PCR (hippocampus) and ELISA (serum) revealed a significant reduction of key proinflammatory cytokines TNFα and IL-1β mRNA in the hippocampus and their protein levels in serum, in addition to IL-6 and IL-12, in the SAR-treated group at 8d in contrast to the vehicle-treated group. These findings suggest that SAR targets some of the key biomarkers of epileptogenesis and modulates neuroinflammatory and nitroxidative pathways that mediate the development of epilepsy. Therefore, SAR can be developed as a potential disease-modifying agent to prevent the development and progression of TLE.
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Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease
Article
Full-text available
  • Apr 2021
Oxidative stress, neuroinflammation and apoptosis are some of the key etiological factors responsible for dopamin(DA)ergic degeneration during Parkinson’s disease (PD), yet the downstream molecular mechanisms underlying neurodegeneration are largely unknown. Recently, a genome-wide association study revealed the FYN gene to be associated with PD, suggesting that Fyn kinase could be a pharmacological target for PD. In this study, we report that Fyn-mediated PKCδ tyrosine (Y311) phosphorylation is a key event preceding its proteolytic activation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinsonism. MPP⁺/MPTP induced Fyn kinase activation in N27 DAergic neuronal cells and the mouse substantia nigra. PKCδ-Y311 phosphorylation by activated Fyn initiates the apoptotic caspase-signaling cascade during DAergic degeneration. Pharmacological attenuation of Fyn activity protected DAergic neurons from MPP⁺-induced degeneration in primary mesencephalic neuronal cultures. We further employed Fyn wild-type and Fyn knockout (KO) mice to confirm whether Fyn is a valid pharmacological target of DAergic neurodegeneration. Primary mesencephalic neurons from Fyn KO mice were greatly protected from MPP⁺-induced DAergic cell death, neurite loss and DA reuptake loss. Furthermore, Fyn KO mice were significantly protected from MPTP-induced PKCδ-Y311 phosphorylation, behavioral deficits and nigral DAergic degeneration. This study thus unveils a mechanism by which Fyn regulates PKCδ′s pro-apoptotic function and DAergic degeneration. Pharmacological inhibitors directed at Fyn activation could prove to be a novel therapeutic target in the delay or halting of selective DAergic degeneration during PD.
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Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke
Article
Full-text available
  • Jan 2021
Microglia-associated neuroinflammation plays an important role in the pathophysiology of ischemic stroke. Microglial activation and polarization, and the inflammatory response mediated by these cells play important roles in the development, progression and outcome of brain injury after ischemic stroke. Currently, there is no effective strategy for treating ischemic stroke in clinical practice. Therefore, it is clinically important to study the role and regulation of microglia in stroke. In this review, we discuss the involvement of microglia in the neuroinflammatory process in ischemic stroke, with the aim of providing a better understanding of the relationship between ischemic stroke and microglia.
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Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
Article
Full-text available
  • Nov 2020
Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.
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Isoform‐specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer’s disease and Lewy body dementias
Article
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Cumulative data suggest the involvement of Fyn tyrosine kinase in Alzheimer's disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also variably found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the postmortem neocortex of patients with AD, as well as those diagnosed as having one of the two main subgroups of LBD: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble β‐amyloid and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human postmortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and further correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings provide further evidence for the involvement of FynT in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.
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Microglia in neurodegenerative diseases
Article
Full-text available
  • Jan 2021
A major feature of neurodegeneration is disruption of central nervous system homeostasis, during which microglia play diverse roles. In the central nervous system, microglia serve as the first line of immune defense and function in synapse pruning, injury repair, homeostasis maintenance, and regulation of brain development through scavenging and phagocytosis. Under pathological conditions or various stimulations, microglia proliferate, aggregate, and undergo a variety of changes in cell morphology, immunophenotype, and function. This review presents the features of microglia, especially their diversity and ability to change dynamically, and reinterprets their role as sensors for multiple stimulations and as effectors for brain aging and neurodegeneration. This review also summarizes some therapeutic approaches for neurodegenerative diseases that target microglia.
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Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients
Article
Full-text available
  • Jul 2020
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a few early detection strategies. We previously proposed the amyloid precursor protein (APP) tyrosine 682 (Tyr682) residue as a valuable target for the development of new innovative pharmacologic or diagnostic interventions in AD. Indeed, when APP is phosphorylated at Tyr682, it is forced into acidic neuronal compartments where it is processed to generate neurotoxic amyloid β peptides. Of interest, Fyn tyrosine kinase (TK) interaction with APP Tyr682 residue increases in AD neurons. Here we proved that when Fyn TK was overexpressed it elicited APP Tyr682 phosphorylation in neurons from healthy donors and promoted the amyloidogenic APP processing with Aβ peptides accumulation and neuronal death. Phosphorylation of APP at Tyr (pAPP-Tyr) increased in neurons of AD patients and AD neurons that exhibited high pAPP-Tyr also had higher Fyn TK activity. Fyn TK inhibition abolished the pAPP-Tyr and reduced Aβ42 secretion in AD neurons. In addition, the multidomain adaptor protein Fe65 controlled the Fyn-mediated pAPP-Tyr, warranting the possibility of targeting the Fe65-APP-Fyn pathway to develop innovative strategies in AD. Altogether, these results strongly emphasize the relevance of focusing on pAPP Tyr682 either for diagnostic purposes, as an early biomarker of the disease, or for pharmacological targeting, using Fyn TKI.
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Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization
Article
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Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposi-tion of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and form neurofibril-lary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperpho-sphorylation and oligomerization as a cell-based tauopathy model. Following the treatments , the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed contrasting results between the two neuronal cultures. This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurode-generative diseases.
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The Role of Astrocytes in CNS Inflammation
Article
  • Aug 2020
  • TRENDS IMMUNOL
Astrocytes are the most abundant cell type in the central nervous system (CNS), performing complex functions in health and disease. It is now clear that multiple astrocyte subsets or activation states (plastic phenotypes driven by intrinsic and extrinsic cues) can be identified, associated to specific genomic programs and functions. The characterization of these subsets and the mechanisms that control them may provide unique insights into the pathogenesis of neurologic diseases, and identify potential targets for therapeutic intervention. In this article, we provide an overview of the role of astrocytes in CNS inflammation, highlighting recent discoveries on astrocyte subsets and the mechanisms that control them.
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