Publications by authors named "Amy K Y Fu"

64 Publications

Instructive roles of astrocytes in hippocampal synaptic plasticity: neuronal activity-dependent regulatory mechanisms.

FEBS J 2021 Apr 17. Epub 2021 Apr 17.

Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

In the adult hippocampus, synaptic plasticity is important for information processing, learning, and memory encoding. Astrocytes, the most common glial cells, play a pivotal role in the regulation of hippocampal synaptic plasticity. While astrocytes were initially described as a homogenous cell population, emerging evidence indicates that in the adult hippocampus, astrocytes are highly heterogeneous and can differentially respond to changes in neuronal activity in a subregion-dependent manner to actively modulate synaptic plasticity. In this review, we summarize how local neuronal activity changes regulate the interactions between astrocytes and synapses, either by modulating the secretion of gliotransmitters and synaptogenic proteins or via contact-mediated signaling pathways. In turn, these specific responses induced in astrocytes mediate the interactions between astrocytes and neurons, thus shaping synaptic communication in the adult hippocampus. Importantly, the activation of astrocytic signaling is required for memory performance including memory acquisition and recall. Meanwhile, the dysregulation of this signaling can cause hippocampal circuit dysfunction in pathological conditions, resulting in cognitive impairment and neurodegeneration. Indeed, reactive astrocytes, which have dysregulated signaling associated with memory, are induced in the brains of patients with Alzheimer's disease (AD) and transgenic mouse model of AD. Emerging technologies that can precisely manipulate and monitor astrocytic signaling in vivo enable the examination of the specific actions of astrocytes in response to neuronal activity changes as well as how they modulate synaptic connections and circuit activity. Such findings will clarify the roles of astrocytes in hippocampal synaptic plasticity and memory in health and disease.
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http://dx.doi.org/10.1111/febs.15878DOI Listing
April 2021

Polygenic Score Models for Alzheimer's Disease: From Research to Clinical Applications.

Front Neurosci 2021 29;15:650220. Epub 2021 Mar 29.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.

The high prevalence of Alzheimer's disease (AD) among the elderly population and its lack of effective treatments make this disease a critical threat to human health. Recent epidemiological and genetics studies have revealed the polygenic nature of the disease, which is possibly explainable by a polygenic score model that considers multiple genetic risks. Here, we systemically review the rationale and methods used to construct polygenic score models for studying AD. We also discuss the associations of polygenic risk scores (PRSs) with clinical outcomes, brain imaging findings, and biochemical biomarkers from both the brain and peripheral system. Finally, we discuss the possibility of incorporating polygenic score models into research and clinical practice along with potential challenges.
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http://dx.doi.org/10.3389/fnins.2021.650220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039467PMC
March 2021

Cytokine signaling convergence regulates the microglial state transition in Alzheimer's disease.

Cell Mol Life Sci 2021 Apr 13. Epub 2021 Apr 13.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Genetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer's disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome-IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.
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http://dx.doi.org/10.1007/s00018-021-03810-0DOI Listing
April 2021

Melanocortin receptor activation alleviates amyloid pathology and glial reactivity in an Alzheimer's disease transgenic mouse model.

Sci Rep 2021 Feb 23;11(1):4359. Epub 2021 Feb 23.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no disease-modifying treatment. AD progression is characterized by cognitive decline, neuroinflammation, and accumulation of amyloid-beta (Aβ) and neurofibrillary tangles in the brain, leading to neuronal and glial dysfunctions. Neuropeptides govern diverse pathophysiological processes and represent key players in AD pathogenesis, regulating synaptic plasticity, glial cell functions and amyloid pathology. Activation of the pro-opiomelanocortin (POMC)-derived neuropeptide and its receptor from the melanocortin receptor (MCR) family have previously been shown to rescue the impairment in hippocampus-dependent synaptic plasticity in the APP/PS1 mouse model of AD. However, the functional roles of MCR signaling in AD conditions, particularly in glial functions, are largely unknown. In this study, we investigated the potential benefits of MCR activation in AD. In APP/PS1 transgenic mice, we demonstrate that MCR activation mediated by the central administration of its agonist D-Tyr MTII substantially reduces Aβ accumulation, while alleviating global inflammation and astrocytic activation, particularly in the hippocampus. MCR activation prominently reduces the A1 subtype of reactive astrocytes, which is considered a key source of astrocytic neurotoxicity in AD. Concordantly, MCR activation suppresses microglial activation, while enhancing their association with amyloid plaques. The blunted activation of microglia may contribute to the reduction in the neurotoxic phenotypes of astrocytes. Importantly, transcriptome analysis reveals that MCR activation restores the impaired homeostatic processes and microglial reactivity in the hippocampus in APP/PS1 mice. Collectively, our findings demonstrate the potential of MCR signaling as therapeutic target for AD.
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http://dx.doi.org/10.1038/s41598-021-83932-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902646PMC
February 2021

Efficient manipulation of gene dosage in human iPSCs using CRISPR/Cas9 nickases.

Commun Biol 2021 Feb 12;4(1):195. Epub 2021 Feb 12.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Center for Stem Cell Research, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

The dysregulation of gene dosage due to duplication or haploinsufficiency is a major cause of autosomal dominant diseases such as Alzheimer's disease. However, there is currently no rapid and efficient method for manipulating gene dosage in a human model system such as human induced pluripotent stem cells (iPSCs). Here, we demonstrate a simple and precise method to simultaneously generate iPSC lines with different gene dosages using paired Cas9 nickases. We first generate a Cas9 nickase variant with broader protospacer-adjacent motif specificity to expand the targetability of double-nicking-mediated genome editing. As a proof-of-concept study, we examine the gene dosage effects on an Alzheimer's disease patient-derived iPSC line that carries three copies of APP (amyloid precursor protein). This method enables the rapid and simultaneous generation of iPSC lines with monoallelic, biallelic, or triallelic knockout of APP. The cortical neurons generated from isogenically corrected iPSCs exhibit gene dosage-dependent correction of disease-associated phenotypes of amyloid-beta secretion and Tau hyperphosphorylation. Thus, the rapid generation of iPSCs with different gene dosages using our method described herein can be a useful model system for investigating disease mechanisms and therapeutic development.
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http://dx.doi.org/10.1038/s42003-021-01722-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881037PMC
February 2021

Quantitative assessment of amyloid-beta phagocytic capacity in an Alzheimer's disease mouse model.

STAR Protoc 2021 Mar 13;2(1):100265. Epub 2021 Jan 13.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Alzheimer's disease is characterized by the deposition of extracellular amyloid-beta (Aβ) plaques. While microglial phagocytosis is a major mechanism through which Aβ is cleared, there is no method for quantitatively assessing Aβ phagocytic capacity of microglia . Here, we present a flow cytometry-based method for investigating the Aβ phagocytic capacity of microglia . This method enables the direct comparison of Aβ phagocytic capacity between different microglial subpopulations as well as the direct isolation of Aβ phagocytic microglia for downstream applications. For complete details on the use and execution of this protocol, please refer to Lau et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2020.100265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811161PMC
March 2021

Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus.

Proc Natl Acad Sci U S A 2021 01 18;118(1). Epub 2020 Dec 18.

Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China;

Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.
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http://dx.doi.org/10.1073/pnas.2020810118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817131PMC
January 2021

p39-associated Cdk5 activity regulates dendritic morphogenesis.

Sci Rep 2020 10 30;10(1):18746. Epub 2020 Oct 30.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Dendrites, branched structures extending from neuronal cell soma, are specialized for processing information from other neurons. The morphogenesis of dendritic structures is spatiotemporally regulated by well-orchestrated signaling cascades. Dysregulation of these processes impacts the wiring of neuronal circuit and efficacy of neurotransmission, which contribute to the pathogeneses of neurological disorders. While Cdk5 (cyclin-dependent kinase 5) plays a critical role in neuronal dendritic development, its underlying molecular control is not fully understood. In this study, we show that p39, one of the two neuronal Cdk5 activators, is a key regulator of dendritic morphogenesis. Pyramidal neurons deficient in p39 exhibit aberrant dendritic morphology characterized by shorter length and reduced arborization, which is comparable to dendrites in Cdk5-deficient neurons. RNA sequencing analysis shows that the adaptor protein, WDFY1 (WD repeat and FYVE domain-containing 1), acts downstream of Cdk5/p39 to regulate dendritic morphogenesis. While WDFY1 is elevated in p39-deficient neurons, suppressing its expression rescues the impaired dendritic arborization. Further phosphoproteomic analysis suggests that Cdk5/p39 mediates dendritic morphogenesis by modulating various downstream signaling pathways, including PI3K/Akt-, cAMP-, or small GTPase-mediated signaling transduction pathways, thereby regulating cytoskeletal organization, protein synthesis, and protein trafficking.
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http://dx.doi.org/10.1038/s41598-020-75264-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603351PMC
October 2020

Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer's disease.

Proc Natl Acad Sci U S A 2020 10 28;117(41):25800-25809. Epub 2020 Sep 28.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China;

Alzheimer's disease (AD) is the most common form of dementia but has no effective treatment. A comprehensive investigation of cell type-specific responses and cellular heterogeneity in AD is required to provide precise molecular and cellular targets for therapeutic development. Accordingly, we perform single-nucleus transcriptome analysis of 169,496 nuclei from the prefrontal cortical samples of AD patients and normal control (NC) subjects. Differential analysis shows that the cell type-specific transcriptomic changes in AD are associated with the disruption of biological processes including angiogenesis, immune activation, synaptic signaling, and myelination. Subcluster analysis reveals that compared to NC brains, AD brains contain fewer neuroprotective astrocytes and oligodendrocytes. Importantly, our findings show that a subpopulation of angiogenic endothelial cells is induced in the brain in patients with AD. These angiogenic endothelial cells exhibit increased expression of angiogenic growth factors and their receptors (i.e., , , and ) and antigen-presentation machinery (i.e., and ). This suggests that these endothelial cells contribute to angiogenesis and immune response in AD pathogenesis. Thus, our comprehensive molecular profiling of brain samples from patients with AD reveals previously unknown molecular changes as well as cellular targets that potentially underlie the functional dysregulation of endothelial cells, astrocytes, and oligodendrocytes in AD, providing important insights for therapeutic development.
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http://dx.doi.org/10.1073/pnas.2008762117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568283PMC
October 2020

Genetic and polygenic risk score analysis for Alzheimer's disease in the Chinese population.

Alzheimers Dement (Amst) 2020 5;12(1):e12074. Epub 2020 Aug 5.

Division of Life Science State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center The Hong Kong University of Science and Technology Clear Water Bay Kowloon Hong Kong China.

Introduction: Dozens of Alzheimer's disease (AD)-associated loci have been identified in European-descent populations, but their effects have not been thoroughly investigated in the Hong Kong Chinese population.

Methods: TaqMan array genotyping was performed for known AD-associated variants in a Hong Kong Chinese cohort. Regression analysis was conducted to study the associations of variants with AD-associated traits and biomarkers. Lasso regression was applied to establish a polygenic risk score (PRS) model for AD risk prediction.

Results: is associated with AD in the Hong Kong Chinese population. Meta-analysis corroborates the AD-protective effect of the rs11218343 C allele. The PRS is developed and associated with AD risk, cognitive status, and AD-related endophenotypes. H157Y might influence the amyloid beta 42/40 ratio and levels of immune-associated proteins in plasma.

Discussion: is associated with AD in the Hong Kong Chinese population. The PRS model can predict AD risk and cognitive status in this population.
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http://dx.doi.org/10.1002/dad2.12074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403835PMC
August 2020

IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer's Disease.

Cell Rep 2020 04;31(3):107530

Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong 518057, China. Electronic address:

Impairment of microglial clearance activity contributes to beta-amyloid (Aβ) pathology in Alzheimer's disease (AD). While the transcriptome profile of microglia directs microglial functions, how the microglial transcriptome can be regulated to alleviate AD pathology is largely unknown. Here, we show that injection of interleukin (IL)-33 in an AD transgenic mouse model ameliorates Aβ pathology by reprogramming microglial epigenetic and transcriptomic profiles to induce a microglial subpopulation with enhanced phagocytic activity. These IL-33-responsive microglia (IL-33RMs) express a distinct transcriptome signature that is highlighted by increased major histocompatibility complex class II genes and restored homeostatic signature genes. IL-33-induced remodeling of chromatin accessibility and PU.1 transcription factor binding at the signature genes of IL-33RM control their transcriptome reprogramming. Specifically, disrupting PU.1-DNA interaction abolishes the microglial state transition and Aβ clearance that is induced by IL-33. Thus, we define a PU.1-dependent transcriptional pathway that drives the IL-33-induced functional state transition of microglia, resulting in enhanced Aβ clearance.
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http://dx.doi.org/10.1016/j.celrep.2020.107530DOI Listing
April 2020

Changes of Protein Phosphorylation Are Associated with Synaptic Functions during the Early Stage of Alzheimer's Disease.

ACS Chem Neurosci 2019 09 29;10(9):3986-3996. Epub 2019 Aug 29.

The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology , Chinese Academy of Sciences; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions , Shenzhen , Guangdong 518055 , China.

Alzheimer's disease is an irreversible neurodegenerative disorder for which we have limited knowledge of the mechanisms underlying its pathogenesis, especially the molecular events that trigger the deterioration of neuronal functions in the early stage. Protein phosphorylation and dephosphorylation are highly dynamic and reversible post-translational modifications that control protein signaling and hence neuronal functions, aberrations of which are implicated in various neurodegenerative diseases including Alzheimer's disease. We conducted a quantitative phosphoproteomic analysis in the brains of APP/PS1 mice, an Aβ-deposition transgenic mouse model, at 3 months old, the stage at which amyloid pathology just initiates. Compared to the wild-type mouse brains, we found that changes in serine phosphorylation were predominant in the APP/PS1 mouse brains, and that the occurrence of proline-directed phosphorylation was most common among the overrepresented phosphopeptides. Further analysis of the 167 phosphoproteins that were significantly up- or downregulated in APP/PS1 mouse brains revealed the enrichment of these proteins in synapse-related pathways. In particular, Western blot analysis validated the increased phosphorylation of chromogranin B, a protein enriched in large dense-core vesicles, in APP/PS1 mouse brains. These findings collectively suggest that changes in the phosphoprotein network may be associated with the deregulation of synaptic functions during the pathogenesis of Alzheimer's disease.
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http://dx.doi.org/10.1021/acschemneuro.9b00190DOI Listing
September 2019

Non-coding variability at the APOE locus contributes to the Alzheimer's risk.

Nat Commun 2019 07 25;10(1):3310. Epub 2019 Jul 25.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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http://dx.doi.org/10.1038/s41467-019-10945-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658518PMC
July 2019

α2-Chimaerin is essential for neural stem cell homeostasis in mouse adult neurogenesis.

Proc Natl Acad Sci U S A 2019 07 17;116(27):13651-13660. Epub 2019 Jun 17.

Division of Life Science, Molecular Neuroscience Center, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China;

Adult hippocampal neurogenesis involves the lifelong generation of neurons. The process depends on the homeostasis of the production of neurons and maintenance of the adult neural stem cell (NSC) pool. Here, we report that α2-chimaerin, a Rho GTPase-activating protein, is essential for NSC homeostasis in adult hippocampal neurogenesis. Conditional deletion of α2-chimaerin in adult NSCs resulted in the premature differentiation of NSCs into intermediate progenitor cells (IPCs), which ultimately depleted the NSC pool and impaired neuron generation. Single-cell RNA sequencing and pseudotime analyses revealed that α2-chimaerin-conditional knockout (α2-CKO) mice lacked a unique NSC subpopulation, termed Klotho-expressing NSCs, during the transition of NSCs to IPCs. Furthermore, α2-CKO led to defects in hippocampal synaptic plasticity and anxiety/depression-like behaviors in mice. Our findings collectively demonstrate that α2-chimaerin plays an essential role in adult hippocampal NSC homeostasis to maintain proper brain function.
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http://dx.doi.org/10.1073/pnas.1903891116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613132PMC
July 2019

Increased Axin expression enhances adult hippocampal neurogenesis and exerts an antidepressant effect.

Sci Rep 2019 02 4;9(1):1190. Epub 2019 Feb 4.

Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Major depressive disorders are emerging health problems that affect millions of people worldwide. However, treatment options and targets for drug development are limited. Impaired adult hippocampal neurogenesis is emerging as a key contributor to the pathology of major depressive disorders. We previously demonstrated that increasing the expression of the multifunctional scaffold protein Axis inhibition protein (Axin) by administration of the small molecule XAV939 enhances embryonic neurogenesis and affects social interaction behaviors. This prompted us to examine whether increasing Axin protein level can enhance adult hippocampal neurogenesis and thus contribute to mood regulation. Here, we report that stabilizing Axin increases adult hippocampal neurogenesis and exerts an antidepressant effect. Specifically, treating adult mice with XAV939 increased the amplification of adult neural progenitor cells and neuron production in the hippocampus under both normal and chronic stress conditions. Furthermore, XAV939 injection in mice ameliorated depression-like behaviors induced by chronic restraint stress. Thus, our study demonstrates that Axin/XAV939 plays an important role in adult hippocampal neurogenesis and provides a potential therapeutic approach for mood-related disorders.
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http://dx.doi.org/10.1038/s41598-018-38103-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362220PMC
February 2019

Synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic strategies.

Pharmacol Ther 2019 03 12;195:186-198. Epub 2018 Nov 12.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China. Electronic address:

Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly population, is characterized by progressive cognitive decline and pathological hallmarks of amyloid plaques and neurofibrillary tangles. However, its pathophysiological mechanisms are poorly understood, and diagnostic tools and interventions are limited. Here, we review recent research on the amyloid hypothesis and beta-amyloid-induced dysfunction of neuronal synapses through distinct cell surface receptors. We also review how tau protein leads to synaptotoxicity through pathological modification, localization, and propagation. Finally, we discuss experimental therapeutics for AD and propose potential applications of disease-modifying strategies targeting synaptic failure for improved treatment of AD.
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http://dx.doi.org/10.1016/j.pharmthera.2018.11.006DOI Listing
March 2019

Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs.

Sci Rep 2018 05 9;8(1):7377. Epub 2018 May 9.

Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer's disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs-ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin-as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.
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http://dx.doi.org/10.1038/s41598-018-25790-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943255PMC
May 2018

Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis.

Proc Natl Acad Sci U S A 2018 02 5;115(8):1697-1706. Epub 2018 Feb 5.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China;

Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the locus (sentinel variant rs73052335, = 1.44 × 10), two common variants, (rs72713460, = 4.36 × 10) and (rs928771, = 3.60 × 10), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the transcript can be observed in the blood of AD subjects. Moreover, the risk variants of and are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the , , and loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of and in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
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http://dx.doi.org/10.1073/pnas.1715554115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828602PMC
February 2018

Homeostatic Scaling of AMPA Receptors by Semaphorin.

Neuron 2017 12;96(5):955-958

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address:

Regulation of AMPA receptors mediates homeostatic scaling. In this issue of Neuron, Wang et al. (2017) identify a new role of secreted semaphorin 3F and elucidate how it triggers synaptic downscaling of AMPA receptors through regulation of the binding of Sema3F holoreceptor complex to AMPA receptors.
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http://dx.doi.org/10.1016/j.neuron.2017.11.025DOI Listing
December 2017

Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development.

Proc Natl Acad Sci U S A 2017 08 31;114(33):E6992-E7001. Epub 2017 Jul 31.

Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China;

The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.
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http://dx.doi.org/10.1073/pnas.1708240114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565463PMC
August 2017

Stimulation of the Hippocampal POMC/MC4R Circuit Alleviates Synaptic Plasticity Impairment in an Alzheimer's Disease Model.

Cell Rep 2016 11;17(7):1819-1831

Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China. Electronic address:

Hippocampal synaptic plasticity is modulated by neuropeptides, the disruption of which might contribute to cognitive deficits observed in Alzheimer's disease (AD). Although pro-opiomelanocortin (POMC)-derived neuropeptides and melanocortin 4 receptor (MC4R) are implicated in hippocampus-dependent synaptic plasticity, how the POMC/MC4R system functions in the hippocampus and its role in synaptic dysfunction in AD are largely unknown. Here, we mapped a functional POMC circuit in the mouse hippocampus, wherein POMC neurons in the cornu ammonis 3 (CA3) activate MC4R in the CA1. Suppression of hippocampal MC4R activity in the APP/PS1 transgenic mouse model of AD exacerbates long-term potentiation impairment, which is alleviated by the replenishment of hippocampal POMC/MC4R activity or activation of hippocampal MC4R-coupled Gs signaling. Importantly, MC4R activation rescues amyloid-β-induced synaptic dysfunction via a Gs/cyclic AMP (cAMP)/PKA/cAMP-response element binding protein (CREB)-dependent mechanism. Hence, disruption of this hippocampal POMC/MC4R circuit might contribute to synaptic dysfunction observed in AD, revealing a potential therapeutic target for the disease.
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http://dx.doi.org/10.1016/j.celrep.2016.10.043DOI Listing
November 2016

IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline.

Proc Natl Acad Sci U S A 2016 May 18;113(19):E2705-13. Epub 2016 Apr 18.

Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;

Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.
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http://dx.doi.org/10.1073/pnas.1604032113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868478PMC
May 2016

Cdk5 Regulates Activity-Dependent Gene Expression and Dendrite Development.

J Neurosci 2015 Nov;35(45):15127-34

Division of Life Science, Molecular Neuroscience Center, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China

Unlabelled: The proper growth and arborization of dendrites in response to sensory experience are essential for neural connectivity and information processing in the brain. Although neuronal activity is important for sculpting dendrite morphology, the underlying molecular mechanisms are not well understood. Here, we report that cyclin-dependent kinase 5 (Cdk5)-mediated transcriptional regulation is a key mechanism that controls activity-dependent dendrite development in cultured rat neurons. During membrane depolarization, Cdk5 accumulates in the nucleus to regulate the expression of a subset of genes, including that of the neurotrophin brain-derived neurotrophic factor, for subsequent dendritic growth. Furthermore, Cdk5 function is mediated through the phosphorylation of methyl-CpG-binding protein 2, a key transcriptional repressor that is mutated in the mental disorder Rett syndrome. These findings collectively suggest that the nuclear import of Cdk5 is crucial for activity-dependent dendrite development by regulating neuronal gene transcription during neural development.

Significance Statement: Neural activity directs dendrite development through the regulation of gene transcription. However, how molecular signals link extracellular stimuli to the transcriptional program in the nucleus remains unclear. Here, we demonstrate that neuronal activity stimulates the translocation of the kinase Cdk5 from the cytoplasmic compartment into the nucleus; furthermore, the nuclear localization of Cdk5 is required for dendrite development in cultured neurons. Genome-wide transcriptome analysis shows that Cdk5 deficiency specifically disrupts activity-dependent gene transcription of bdnf. The action of Cdk5 is mediated through the modulation of the transcriptional repressor methyl-CpG-binding protein 2. Therefore, this study elucidates the role of nuclear Cdk5 in the regulation of activity-dependent gene transcription and dendritic growth.
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http://dx.doi.org/10.1523/JNEUROSCI.1443-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605353PMC
November 2015

S-nitrosylation-dependent proteasomal degradation restrains Cdk5 activity to regulate hippocampal synaptic strength.

Nat Commun 2015 Oct 27;6:8665. Epub 2015 Oct 27.

Divison of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.

Precise regulation of synaptic strength requires coordinated activity and functions of synaptic proteins, which is controlled by a variety of post-translational modification. Here we report that S-nitrosylation of p35, the activator of cyclin-dependent kinase 5 (Cdk5), by nitric oxide (NO) is important for the regulation of excitatory synaptic strength. While blockade of NO signalling results in structural and functional synaptic deficits as indicated by reduced mature dendritic spine density and surface expression of glutamate receptor subunits, phosphorylation of numerous synaptic substrates of Cdk5 and its activity are aberrantly upregulated following reduced NO production. The results show that the NO-induced reduction in Cdk5 activity is mediated by S-nitrosylation of p35, resulting in its ubiquitination and degradation by the E3 ligase PJA2. Silencing p35 protein in hippocampal neurons partially rescues the NO blockade-induced synaptic deficits. These findings collectively demonstrate that p35 S-nitrosylation by NO signalling is critical for regulating hippocampal synaptic strength.
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http://dx.doi.org/10.1038/ncomms9665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639907PMC
October 2015

Axin Regulates Dendritic Spine Morphogenesis through Cdc42-Dependent Signaling.

PLoS One 2015 23;10(7):e0133115. Epub 2015 Jul 23.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Guangdong Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China.

During development, scaffold proteins serve as important platforms for orchestrating signaling complexes to transduce extracellular stimuli into intracellular responses that regulate dendritic spine morphology and function. Axin ("axis inhibitor") is a key scaffold protein in canonical Wnt signaling that interacts with specific synaptic proteins. However, the cellular functions of these protein-protein interactions in dendritic spine morphology and synaptic regulation are unclear. Here, we report that Axin protein is enriched in synaptic fractions, colocalizes with the postsynaptic marker PSD-95 in cultured hippocampal neurons, and interacts with a signaling protein Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in synaptosomal fractions. Axin depletion by shRNA in cultured neurons or intact hippocampal CA1 regions significantly reduced dendritic spine density. Intriguingly, the defective dendritic spine morphogenesis in Axin-knockdown neurons could be restored by overexpression of the small Rho-GTPase Cdc42, whose activity is regulated by CaMKII. Moreover, pharmacological stabilization of Axin resulted in increased dendritic spine number and spontaneous neurotransmission, while Axin stabilization in hippocampal neurons reduced the elimination of dendritic spines. Taken together, our findings suggest that Axin promotes dendritic spine stabilization through Cdc42-dependent cytoskeletal reorganization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133115PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512687PMC
May 2016

Emerging roles of Axin in cerebral cortical development.

Front Cell Neurosci 2015 8;9:217. Epub 2015 Jun 8.

Division of Life Science, Molecular Neuroscience Center and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology Hong Kong, China.

Proper functioning of the cerebral cortex depends on the appropriate production and positioning of neurons, establishment of axon-dendrite polarity, and formation of proper neuronal connectivity. Deficits in any of these processes greatly impair neural functions and are associated with various human neurodevelopmental disorders including microcephaly, cortical heterotopias, and autism. The application of in vivo manipulation techniques such as in utero electroporation has resulted in significant advances in our understanding of the cellular and molecular mechanisms that underlie neural development in vivo. Axin is a scaffold protein that regulates neuronal differentiation and morphogenesis in vitro. Recent studies provide novel insights into the emerging roles of Axin in gene expression and cytoskeletal regulation during neurogenesis, neuronal polarization, and axon formation. This review summarizes current knowledge on Axin as a key molecular controller of cerebral cortical development.
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http://dx.doi.org/10.3389/fncel.2015.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458687PMC
June 2015

Overproduction of upper-layer neurons in the neocortex leads to autism-like features in mice.

Cell Rep 2014 Dec 26;9(5):1635-1643. Epub 2014 Nov 26.

Division of Life Science, Center for Stem Cell Research, Molecular Neuroscience Center, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China. Electronic address:

The functional integrity of the neocortex depends upon proper numbers of excitatory and inhibitory neurons; however, the consequences of dysregulated neuronal production during the development of the neocortex are unclear. As excess cortical neurons are linked to the neurodevelopmental disorder autism, we investigated whether the overproduction of neurons leads to neocortical malformation and malfunction in mice. We experimentally increased the number of pyramidal neurons in the upper neocortical layers by using the small molecule XAV939 to expand the intermediate progenitor population. The resultant overpopulation of neurons perturbs development of dendrites and spines of excitatory neurons and alters the laminar distribution of interneurons. Furthermore, these phenotypic changes are accompanied by dysregulated excitatory and inhibitory synaptic connection and balance. Importantly, these mice exhibit behavioral abnormalities resembling those of human autism. Thus, our findings collectively suggest a causal relationship between neuronal overproduction and autism-like features, providing developmental insights into the etiology of autism.
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http://dx.doi.org/10.1016/j.celrep.2014.11.003DOI Listing
December 2014

p35 regulates the CRM1-dependent nucleocytoplasmic shuttling of nuclear hormone receptor coregulator-interacting factor 1 (NIF-1).

PLoS One 2014 16;9(10):e110584. Epub 2014 Oct 16.

Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC)-interacting factor 1 (NIF-1), is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110584PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199748PMC
December 2015

Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex.

Nat Commun 2014 Sep 5;5:4826. Epub 2014 Sep 5.

1] Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China [2] Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China [3] State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

During cerebral cortex development, pyramidal neurons migrate through the intermediate zone and integrate into the cortical plate. These neurons undergo the multipolar-bipolar transition to initiate radial migration. While perturbation of this polarity acquisition leads to cortical malformations, how this process is initiated and regulated is largely unknown. Here we report that the specific upregulation of the Rap1 guanine nucleotide exchange factor, RapGEF2, in migrating neurons corresponds to the timing of this polarity transition. In utero electroporation and live-imaging studies reveal that RapGEF2 acts on the multipolar-bipolar transition during neuronal migration via a Rap1/N-cadherin pathway. Importantly, activation of RapGEF2 is controlled via phosphorylation by a serine/threonine kinase Cdk5, whose activity is largely restricted to the radial migration zone. Thus, the specific expression and Cdk5-dependent phosphorylation of RapGEF2 during multipolar-bipolar transition within the intermediate zone are essential for proper neuronal migration and wiring of the cerebral cortex.
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http://dx.doi.org/10.1038/ncomms5826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164783PMC
September 2014

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer's disease.

Proc Natl Acad Sci U S A 2014 Jul 23;111(27):9959-64. Epub 2014 Jun 23.

Division of Life Science,Molecular Neuroscience Center,State Key Laboratory of Molecular Neuroscience, and

Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.
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http://dx.doi.org/10.1073/pnas.1405803111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103318PMC
July 2014