Two cyclin-dependent kinase pathways are essential for polarized trafficking of presynaptic components.

Polarized trafficking of synaptic proteins to axons and dendrites is crucial to neuronal function. Through forward genetic analysis in C. elegans, we identified a cyclin (CYY-1) and a cyclin-dependent Pctaire kinase (PCT-1) necessary for targeting presynaptic components to the axon. Another cyclin-dependent kinase, CDK-5, and its activator p35, act in parallel to and partially redundantly with the CYY-1/PCT-1 pathway. Synaptic vesicles and active zone proteins mostly mislocalize to dendrites in animals defective for both PCT-1 and CDK-5 pathways. Unlike the kinesin-3 motor, unc-104/Kif1a mutant, cyy-1 cdk-5 double mutants have no reduction in anterogradely moving synaptic vesicle precursors (SVPs) as observed by dynamic imaging. Instead, the number of retrogradely moving SVPs is dramatically increased. Furthermore, this mislocalization defect is suppressed by disrupting the retrograde motor, the cytoplasmic dynein complex. Thus, PCT-1 and CDK-5 pathways direct polarized trafficking of presynaptic components by inhibiting dynein-mediated retrograde transport and setting the balance between anterograde and retrograde motors.

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

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.

Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification.

INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. HIGHLIGHTS: We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.

A blood-based multi-pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups.

INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed.

Receptor-ligand interaction controls microglial chemotaxis and amelioration of Alzheimer's disease pathology.

Microglia maintain brain homeostasis through their ability to survey and phagocytose danger-associated molecular patterns (DAMPs). In Alzheimer's disease (AD), microglial phagocytic clearance regulates the turnover of neurotoxic DAMPs including amyloid beta (Aß) and hyperphosphorylated tau. To mediate DAMP clearance, microglia express a repertoire of surface receptors to sense DAMPs; the activation of these receptors subsequently triggers a chemotaxis-to-phagocytosis functional transition in microglia. Therefore, the interaction between microglial receptors and DAMPs plays a critical role in controlling microglial DAMP clearance and AD pathogenesis. However, there is no comprehensive overview on how microglial sensome receptors interact with DAMPs and regulate various microglial functions, including chemotaxis and phagocytosis. In this review, we discuss the important axes of receptor-ligand interaction that control different microglial functions and their roles in AD pathogenesis. First, we summarize how the accumulation and structural changes of DAMPs trigger microglial functional impairment, including impaired DAMP clearance and aberrant synaptic pruning, in AD. Then, we discuss the important receptor-ligand axes that restore microglial DAMP clearance in AD and aging. These findings suggest that targeting microglial chemotaxis-the first critical step of the microglial chemotaxis-to-phagocytosis state transition-can promote microglial DAMP clearance in AD. Thus, our review highlights the importance of microglial chemotaxis in promoting microglial clearance activity in AD. Further detailed investigations are essential to identify the molecular machinery that controls microglial chemotaxis in AD.

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

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., EGFL7, FLT1, and VWF) and antigen-presentation machinery (i.e., B2M and HLA-E). 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.

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

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-1ß, 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.

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

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.

Large-scale plasma proteomic profiling identifies a high-performance biomarker panel for Alzheimer's disease screening and staging.

INTRODUCTION: Blood proteins are emerging as candidate biomarkers for Alzheimer's disease (AD). We systematically profiled the plasma proteome to identify novel AD blood biomarkers and develop a high-performance, blood-based test for AD. METHODS: We quantified 1160 plasma proteins in a Hong Kong Chinese cohort by high-throughput proximity extension assay and validated the results in an independent cohort. In subgroup analyses, plasma biomarkers for amyloid, tau, phosphorylated tau, and neurodegeneration were used as endophenotypes of AD. RESULTS: We identified 429 proteins that were dysregulated in AD plasma. We selected 19 "hub proteins" representative of the AD plasma protein profile, which formed the basis of a scoring system that accurately classified clinical AD (area under the curve  = 0.9690-0.9816) and associated endophenotypes. Moreover, specific hub proteins exhibit disease stage-dependent dysregulation, which can delineate AD stages. DISCUSSION: This study comprehensively profiled the AD plasma proteome and serves as a foundation for a high-performance, blood-based test for clinical AD screening and staging.

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

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 APOE locus (sentinel variant rs73052335, P = 1.44 × 10-14), two common variants, GCH1 (rs72713460, P = 4.36 × 10-5) and KCNJ15 (rs928771, P = 3.60 × 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 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 APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.

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

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.

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

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 ß-amyloid (Aß) 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 Aß levels and amyloid plaque deposition by promoting the recruitment and Aß 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-1ß, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.

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

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-ß oligomers (Aß), 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.

Cdk5 Regulates Activity-Dependent Gene Expression and Dendrite Development.

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.

Coronin 6 regulates acetylcholine receptor clustering through modulating receptor anchorage to actin cytoskeleton.

The maintenance of a high density of neurotransmitter receptors at the postsynaptic apparatus is critical for efficient neurotransmission. Acetylcholine receptors (AChRs) are neurotransmitter receptors densely packed on the postsynaptic muscle membrane at the neuromuscular junction (NMJ) via anchoring onto the actin cytoskeletal network. However, how the receptor-associated actin is coordinately regulated is not fully understood. We report here that Coronin 6, a newly identified member of the coronin family, is highly enriched at adult NMJs and regulates AChR clustering through modulating the interaction between receptors and the actin cytoskeletal network. Experiments with cultured myotubes reveal that Coronin 6 is important for both agrin- and laminin-induced AChR clustering. Furthermore, Coronin 6 forms a complex with AChRs and actin in a manner dependent on its C-terminal region and a conserved Arg(29) residue at the N terminus, both of which are critical for the cytoskeletal anchorage of AChRs. Importantly, in vivo knockdown of Coronin 6 in mouse skeletal muscle fibers leads to destabilization of AChR clusters. Together, these findings demonstrate that Coronin 6 is a critical regulator of AChR clustering at the postsynaptic region of the NMJs through modulating the receptor-anchored actin cytoskeleton.

Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition.

The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics.

Melanocortin-4 receptor regulates hippocampal synaptic plasticity through a protein kinase A-dependent mechanism.

Learning and memory require orchestrated regulation of both structural and functional synaptic plasticity in the hippocampus. While a neuropeptide alpha-melanocyte-stimulating hormone, α-MSH, has been implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored. In this study, we report that activation of MC4R enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA receptors. We show that activation of postsynaptic MC4R increases the number of mature dendritic spines and enhances surface expression of AMPA receptor subunit GluA1, resulting in synaptic accumulation of GluA1-containing AMPA receptors. Moreover, MC4R stimulates surface GluA1 trafficking through phosphorylation of GluA1 at Ser845 in a Gα(s)-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolishes the MC4R-mediated enhancement of neurotransmission and hippocampal long-term potentiation. Importantly, in vivo application of MC4R agonists increases LTP in the mouse hippocampal CA1 region. These findings reveal that MC4R in the hippocampus plays a critical role in the regulation of structural and functional plasticity.

Ankyrin repeat-rich membrane spanning protein (kidins220) is required for neurotrophin and ephrin receptor-dependent dendrite development.

Dendrites are the primary sites on neurons for receiving and integrating inputs from their presynaptic partners. Defects in dendrite development perturb the formation of neural circuitry and impair information processing in the brain. Extracellular cues are important for shaping the dendritic morphogenesis, but the underlying molecular mechanisms are not well understood. In this study, we examined the role of ARMS (ankyrin repeat-rich membrane spanning protein), also known as Kidins220 (kinase D-interacting substrate of 220 kDa), previously identified as a downstream target of neurotrophin and ephrin receptors, in dendrite development. We report here that knockdown of ARMS/Kidins220 by in utero electroporation impairs dendritic branching in mouse cerebral cortex, and silencing of ARMS/Kidins220 in primary rat hippocampal neurons results in a significant decrease in the length, number, and complexity of the dendritic arbors. Overexpression of cell surface receptor tyrosine kinases, including TrkB and EphB2, in ARMS/Kidins220-deficient neurons can partially rescue the defective dendritic phenotype. More importantly, we show that PI3K (phosphoinositide-3-kinase)- and Akt-mediated signaling pathway is crucial for ARMS/Kidins220-dependent dendrite development. Furthermore, loss of ARMS/Kidins220 significantly reduced the clustering of EphB2 receptor signaling complex in neurons. Our results collectively suggest that ARMS/Kidins220 is a key player in organizing the signaling complex to transduce the extracellular stimuli to cellular responses during dendrite development.

Axin: an emerging key scaffold at the synapse.

Neurons communicate through neurotransmission at the synapse. Precise regulation of the synaptic structure and signaling during the formation and remodeling of synapses is vital for information processing between neurons. Scaffold proteins play key roles in synapses by tethering the signaling cascades spatially and temporally to ensure proper brain functioning. This review summarizes the recent evidence indicating that Axin, a scaffold protein, plays a central role in orchestrating presynaptic and postsynaptic signaling complexes to regulate synapse development and plasticity in the central nervous system.

Cdk5 phosphorylates a component of the HDAC complex and regulates histone acetylation during neuronal cell death.

Cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for regulating neural development and neuronal survival. Dysregulation of Cdk5 is associated with abnormal expression of cell cycle-related proteins during neuronal apoptosis. We have previously found that p35, a Cdk5 activator, interacts with mSds3, an integral component of the histone deacetylase complex in vitro, suggesting a functional role of Cdk5 in gene regulation through modulation of chromatin integrity. In this study, we further demonstrate that Cdk5-dependent phosphorylation of mSds3 at Ser228 occurs in mouse brain nuclei. The expression of mSds3 protein and its interaction with Cdk5 activators is developmentally regulated in the mouse brain. Importantly, our findings suggest that the ability of Cdk5 to regulate activity deprivation-induced apoptosis of cerebellar granule neurons is likely mediated by the regulation of histone acetylation. Suppression of Cdk5 not only attenuates the induction of histone H3 acetylation and the aberrant upregulation of cyclin proteins in neurons after activity deprivation, but also results in protection of neurons against apoptotic cell death. Taken together, our findings suggest that Cdk5 regulates neuronal survival by precise epigenetic control through modulation of histone acetylation.