The vast majority of Alzheimer's disease (AD) cases are late onset with progressive synapse loss and neurodegeneration. Although the amyloid hypothesis has generated great insights into mechanism, several lines evidence indicate that other risk factors might precondition brain to toxicity. Here, we show deletion a major lipoprotein receptor, low-density receptor-related protein 1 (LRP1), in forebrain neurons mice leads global defect lipid metabolism characterized by decreased levels...

Alzheimer's disease and other tauopathies have recently been clustered with a group of nervous system disorders termed protein misfolding diseases. The common element established between these is their requirement for processing by the chaperone complex. It now clear that individual components system, such as Hsp70 Hsp90, exist in an intricate signaling network exerts pleiotropic effects on host substrates. Therefore, we endeavored to identify new compounds can specifically regulate family....

The three human alleles of apolipoprotein E (APOE) differentially influence outcome after CNS injury and affect one's risk developing Alzheimer's disease (AD). It remains unclear how ApoE isoforms contribute to various AD-related pathological changes (e.g., amyloid plaques synaptic neuron loss). Here, we systematically examined whether apoE (E2, E3, E4) exhibit differential effects on dendritic spine density morphology in APOE targeted replacement (TR) mice, which lack AD changes. Using...

Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein ligand Reelin important normal plasticity, dendritic morphology, cognitive function; however, vivo effect enhanced signaling on function wild-type mice unknown. present studies test hypothesis enhancement can alter ultimately influence processes learning...

Three neuronal pentraxins are expressed in brain, the membrane-bound “neuronal pentraxin receptor” (NPR) and secreted proteins NP1 NARP (i.e., NP2). Neuronal bind to AMPARs at excitatory synapses play important, well-documented roles activity-dependent regulation of neural circuits via this binding activity. However, it is unknown whether perform beyond modulating postsynaptic AMPAR-dependent plasticity, they may even act inhibitory synapses. Here, we show that NPR non-neuronal cells...

Significance Interactions between transsynaptic cell-adhesion molecules enable formation of trillions synaptic connections that wire neurons into vast functional circuits. Neurexins are presynaptic bind to diverse postsynaptic ligands, and genetically linked neuropsychiatric disorders. Here we show CA10, a secreted, catalytically inactive carbonic-anhydrase homolog, binds in cis configuration all neurexins, including Nrxn1γ. In cultured neurons, CA10 enhances surface transport indicating the...

Neurexins are well-characterized presynaptic cell adhesion molecules that engage multifarious postsynaptic ligands and organize diverse synapse properties. However, the precise synaptic localization of neurexins remains enigmatic. Using super-resolution microscopy, we demonstrate neurexin-1 forms discrete nanoclusters at excitatory synapses, revealing a novel organizational feature architecture. Synapses generally contain single nanocluster comprises more than four also includes neurexin-2...

Abstract Disrupted synaptic inhibition is implicated in neuropsychiatric disorders, yet the molecular mechanisms that shape and sustain inhibitory synapses are poorly understood. Here, we show through rescue experiments performed using Neurexin-3 conditional knockout mice alternative splicing at SS2 SS4 regulates release probability, but not number, of olfactory bulb prefrontal cortex independent sex. splice variants mediate binding to dystroglycan enable synapse function, whereas don’t...

Neurexins are widely thought to promote synapse formation and organize properties. Here we found that in contrast neurexin-1 neurexin-3, neurexin-2 unexpectedly restricts formation. In the hippocampus, constitutive or neuron-specific deletions of nearly doubled strength excitatory CA3➔CA1 region synaptic connections markedly increased their release probability. No effect on inhibitory synapses was detected. Stochastic optical reconstruction microscopy (STORM) superresolution revealed...

Disabled-1 (Dab1) is an adaptor protein that obligate effector of the Reelin signaling pathway, and critical for neuronal migration dendrite outgrowth during development. Components pathway are highly expressed development, but also continue to be in adult brain. Here we investigated detail expression pattern Dab1 postnatal forebrain, determined it excitatory as well inhibitory neurons. was found localized different cellular compartments, including soma, dendrites, presynaptic postsynaptic...

The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning memory. Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, behavioral features that are associated with schizophrenia. HRM subtle morphological defects including reductions in spine density, altered plasticity deficits associative memory pre-pulse inhibition. present studies test hypothesis vivo elevation levels can rescue phenotypes...

Emerging concepts in developmental biology, such as facilitated variation and dynamical patterning modules, address a major shortcoming of the Modern Synthesis Biology: how genotypic is transduced into functional yet diverse phenotypic variation. Still, we lack theory to explain at cellular tissue level coordinated whole-organism level, especially priority functions change over an individual's lifetime are influenced by environmental Here, propose that interactions among limited subset...

The lipoprotein receptor system in the hippocampus is intimately involved modulation of synaptic transmission and plasticity. association specific apoE isoform expression with human neurodegenerative disorders has focused attention on role these isoforms receptor-dependent modulation. In present study, we used apoE2, apoE3 apoE4 targeted replacement (TR) mice along recombinant to determine area CA1 function. While unaffected by isoform, long-term potentiation (LTP) significantly enhanced TR...

The microtubule-associated protein tau, which becomes hyperphosphorylated and pathologically aggregates in a number of these diseases, is extremely sensitive to manipulations chaperone signaling. For example, Hsp90 inhibitors can reduce the levels tau transgenic mouse models tauopathy. Because this, we hypothesized that accessory proteins, termed co-chaperones, could also affect stability. Perhaps by identifying new therapeutics be designed specifically target proteins facilitate clearance....

Target-based drug discovery for Alzheimer's disease (AD) centered on modulation of the amyloid β peptide has met with limited success. Therefore, recent efforts have focused targeting microtubule-associated protein tau. Tau pathologically accumulates in more than 15 neurodegenerative diseases and is most closely linked postsymptomatic progression AD. We endeavored to identify compounds that decrease tau stability rather prevent its aggregation. An extract from Myrica cerifera...

Background Apolipoprotein E receptor 2 (ApoEr2) is a postsynaptic protein involved in long-term potentiation (LTP), learning, and memory through unknown mechanisms. We examined the biological effects of ApoEr2 on synapse dendritic spine formation—processes critical for learning memory. Methodology/Principal Findings In heterologous co-culture assay, overexpression COS7 cells significantly increased colocalization with synaptophysin primary hippocampal neurons, suggesting that promotes...

At tripartite synapses, astrocytes enmesh synaptic contacts, but how contribute to the formation, maturation and plasticity of synapses remains elusive. Here we show that both neurons abundantly express neurexin-1, a presynaptic adhesion molecule controls properties. Using super-resolution imaging, demonstrate neuronal astrocytic neurexin-1 form discrete nanoclusters at excitatory synapses. We find distinct patterns heparan sulfate modification alternative splicing confer onto different...

Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal UBE3A gene. Ube3a protein identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating localization and basal expression profiles in mouse models, molecular mechanisms whereby deficiency results AS are enigmatic. Using vitro vivo systems we show dramatic changes following synaptic activation. In primary neuronal culture, depolarization was...

α- and β-neurexins are extensively alternatively spliced, presynaptic cell-adhesion molecules that thought to organize synapse assembly. However, recent data revealed that, in the hippocampus vivo, deletion of one neurexin isoform, Nrxn2 , surprisingly increased excitatory numbers enhanced their release probability, suggesting restricts, instead enabling, To delineate synaptic function mechanism action we examined cultured hippocampal neurons as a reduced system. In heterologous formation...

The cellular and molecular mechanisms responsible for the development of inner retinal circuitry are poorly understood. Reelin apolipoprotein E (apoE), ligands apoE receptor 2 (ApoER2), involved in degeneration, respectively. Here we describe function ApoER2 developing adult retina. expression was highest during postnatal synaptic considerably lower mature Both adult, expressed by A-II amacrine cells. knock-out (KO) mice had rod bipolar morphogenic defects, altered dendritic development,...

Astrocytes exert multifarious roles in the formation, regulation, and function of synapses brain, but mechanisms involved remain unclear. Interestingly, astrocytes abundantly express neuroligins, postsynaptic adhesion molecules that bind to presynaptic neurexins. A pioneering recent study reported loss-of-function neuroligins impairs excitatory synapse formation astrocyte morphogenesis. This suggested a crucial synaptic for astrocytic was puzzling given constitutive neuroligin deletions do...

Summary 1. Evolutionary medicine seeks to understand whether and what extent aspects of human disease are adaptations for coping with infections or injuries, the consequence mismatches between modern ancestral environments. Ecological immunology by comparison focuses largely on how organisms balance investments in immune defences against other traits (e.g., cognitive reproductive functions) maximize fitness. 2. Here we address potential benefit merging these two young disciplines reviewing...