A concerted neuron-astrocyte program declines in ageing and schizophrenia.

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.

Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3ß (GSK3ß). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca2+ to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3ß. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases.

Amyloid-ß Oligomer-Induced Electrophysiological Mechanisms and Electrical Impedance Changes in Neurons.

Amyloid plays a critical role in the pathogenesis of Alzheimer's disease (AD) and can aggregate to form oligomers and fibrils in the brain. There is increasing evidence that highly toxic amyloid-ß oligomers (AßOs) lead to tau protein aggregation, hyperphosphorylation, neuroinflammation, neuronal loss, synaptic loss, and dysfunction. Although the effects of AßOs on neurons have been investigated using conventional biochemical experiments, there are no established criteria for electrical evaluation. To this end, we explored electrophysiological changes in mouse hippocampal neurons (HT22) following exposure to AßOs and/or naringenin (Nar, a flavonoid compound) using electrical impedance spectroscopy (EIS). AßO-induced HT22 showed a decreased impedance amplitude and increased phase angle, and the addition of Nar reversed these changes. The characteristic frequency was markedly increased with AßO exposure, which was also reversed by Nar. The AßOs decreased intranuclear and cytoplasmic resistance and increased nucleus resistance and extracellular capacitance. Overall, the innovative construction of the eight-element CPE-equivalent circuit model further reflects that the pseudo-capacitance of the cell membrane and cell nucleus was increased in the AßO-induced group. This study conclusively revealed that AßOs induce cytotoxic effects by disrupting the resistance characteristics of unit membranes. The results further support that EIS is an effective technique for evaluating AßO-induced neuronal damage and microscopic electrical distinctions in the sub-microscopic structure of reactive cells.

Structural and biochemical alterations in dendritic spines as key mechanisms for severe mental illnesses.

Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.

Mechanisms of age-related hearing loss at the auditory nerve central synapses and postsynaptic neurons in the cochlear nucleus.

Sound information is transduced from mechanical vibration to electrical signals in the cochlea, conveyed to and further processed in the brain to form auditory perception. During the process, spiral ganglion neurons (SGNs) are the key cells that connect the peripheral and central auditory systems by receiving information from hair cells in the cochlea and transmitting it to neurons of the cochlear nucleus (CN). Decades of research in the cochlea greatly improved our understanding of SGN function under normal and pathological conditions, especially about the roles of different subtypes of SGNs and their peripheral synapses. However, it remains less clear how SGN central terminals or auditory nerve (AN) synapses connect to CN neurons, and ultimately how peripheral pathology links to structural alterations and functional deficits in the central auditory nervous system. This review discusses recent progress about the morphological and physiological properties of different subtypes of AN synapses and associated postsynaptic CN neurons, their changes during aging, and the potential mechanisms underlying age-related hearing loss.

Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.

Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.

Neuronal transcriptome, tau and synapse loss in Alzheimer's knock-in mice require prion protein.

BACKGROUND: Progression of Alzheimer's disease leads to synapse loss, neural network dysfunction and cognitive failure. Accumulation of protein aggregates and brain immune activation have triggering roles in synaptic failure but the neuronal mechanisms underlying synapse loss are unclear. On the neuronal surface, cellular prion protein (PrPC) is known to be a high-affinity binding site for Amyloid-ß oligomers (Aßo). However, PrPC's dependence in knock-in AD models for tau accumulation, transcriptomic alterations and imaging biomarkers is unknown. METHODS: The necessity of PrPC was examined as a function of age in homozygous AppNL-G-F/hMapt double knock-in mice (DKI). Phenotypes of AppNL-G-F/hMapt mice with a deletion of Prnp expression (DKI; Prnp-/-) were compared with DKI mice with intact Prnp, mice with a targeted deletion of Prnp (Prnp-/-), and mice with intact Prnp (WT). Phenotypes examined included behavioral deficits, synapse loss by PET imaging, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seq transcriptomic profiling. RESULTS: By 9 months age, DKI mice showed learning and memory impairment, but DKI; Prnp-/- and Prnp-/- groups were indistinguishable from WT. Synapse loss in DKI brain, measured by [18F]SynVesT-1 SV2A PET or anti-SV2A immunohistology, was prevented by Prnp deletion. Accumulation of Tau phosphorylated at aa 217 and 202/205, C1q tagging of synapses, and dystrophic neurites were all increased in DKI mice but each decreased to WT levels with Prnp deletion. In contrast, astrogliosis, microgliosis and Aß levels were unchanged between DKI and DKI; Prnp-/- groups. Single-nuclei transcriptomics revealed differential expression in neurons and glia of DKI mice relative to WT. For DKI; Prnp-/- mice, the majority of neuronal genes differentially expressed in DKI mice were no longer significantly altered relative to WT, but most glial DKI-dependent gene expression changes persisted. The DKI-dependent neuronal genes corrected by Prnp deletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in the Prnp-/- or the DKI; Prnp-/- groups. CONCLUSIONS: Thus, PrPC-dependent synapse loss, phospho-tau accumulation and neuronal gene expression in AD mice can be reversed without clearing Aß plaque or preventing gliotic reaction. This supports targeting the Aßo-PrPC interaction to prevent Aßo-neurotoxicity and pathologic tau accumulation in AD.

Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease.

Importance: Factors associated with synapse loss beyond amyloid-ß plaques and neurofibrillary tangles may more closely correlate with the emergence of cognitive deficits in Alzheimer disease (AD) and be relevant for early therapeutic intervention. Objective: To investigate whether accumulation of tau oligomers in synapses is associated with excessive synapse elimination by microglia or astrocytes and with cognitive outcomes (dementia vs no dementia [hereinafter termed resilient]) of individuals with equal burdens of AD neuropathologic changes at autopsy. Design, Setting, and Participants: This cross-sectional postmortem study included 40 human brains from the Massachusetts Alzheimer Disease Research Center Brain Bank with Braak III to IV stages of tau pathology but divergent antemortem cognition (dementia vs resilient) and cognitively normal controls with negligible AD neuropathologic changes. The visual cortex, a region without tau tangle deposition at Braak III to IV stages, was assessed after expansion microscopy to analyze spatial relationships of synapses with microglia and astrocytes. Participants were matched for age, sex, and apolipoprotein E status. Evidence of Lewy bodies, TDP-43 aggregates, or other lesions different from AD neuropathology were exclusion criteria. Tissue was collected from July 1998 to November 2020, and analyses were conducted from February 1, 2022, through May 31, 2023. Main Outcomes and Measures: Amyloid-ß plaques, tau neuropil thread burden, synapse density, tau oligomers in synapses, and internalization of tau oligomer-tagged synapses by microglia and astrocytes were quantitated. Analyses were performed using 1-way analysis of variance for parametric variables and the Kruskal-Wallis test for nonparametric variables; between-group differences were evaluated with Holm-Sídák tests. Results: Of 40 included participants (mean [SD] age at death, 88 [8] years; 21 [52%] male), 19 had early-stage dementia with Braak stages III to IV, 13 had resilient brains with similar Braak stages III to IV, and 8 had no dementia (Braak stages 0-II). Brains with dementia but not resilient brains had substantial loss of presynaptic (43%), postsynaptic (33%), and colocalized mature synaptic elements (38%) compared with controls and significantly higher percentages of mature synapses internalized by IBA1-positive microglia (mean [SD], 13.3% [3.9%] in dementia vs 2.6% [1.9%] in resilient vs 0.9% [0.5%] in control; P < .001) and by GFAP-positive astrocytes (mean [SD], 17.2% [10.9%] in dementia vs 3.7% [4.0%] in resilient vs 2.7% [1.8%] in control; P = .001). In brains with dementia but not in resilient brains, tau oligomers more often colocalized with synapses, and the proportions of tau oligomer-containing synapses inside microglia (mean [SD] for presynapses, mean [SD], 7.4% [1.8%] in dementia vs 5.1% [1.9%] resilient vs 3.7% [0.8%] control; P = .006; and for postsynapses 11.6% [3.6%] dementia vs 6.8% [1.3%] resilient vs 7.4% [2.5%] control; P = .001) and astrocytes (mean [SD] for presynapses, 7.0% [2.1%] dementia vs 4.3% [2.2%] resilient vs 4.0% [0.7%] control; P = .001; and for postsynapses, 7.9% [2.2%] dementia vs 5.3% [1.8%] resilient vs 3.0% [1.5%] control; P < .001) were significantly increased compared with controls. Those changes in brains with dementia occurred in the absence of tau tangle deposition in visual cortex. Conclusion and Relevance: The findings from this cross-sectional study suggest that microglia and astrocytes may excessively engulf synapses in brains of individuals with dementia and that the abnormal presence of tau oligomers in synapses may serve as signals for increased glial-mediated synapse elimination and early loss of brain function in AD.

Transcriptional linkage analysis with in vivo AAV-Perturb-seq.

The ever-growing compendium of genetic variants associated with human pathologies demands new methods to study genotype-phenotype relationships in complex tissues in a high-throughput manner1,2. Here we introduce adeno-associated virus (AAV)-mediated direct in vivo single-cell CRISPR screening, termed AAV-Perturb-seq, a tuneable and broadly applicable method for transcriptional linkage analysis as well as high-throughput and high-resolution phenotyping of genetic perturbations in vivo. We applied AAV-Perturb-seq using gene editing and transcriptional inhibition to systematically dissect the phenotypic landscape underlying 22q11.2 deletion syndrome3,4 genes in the adult mouse brain prefrontal cortex. We identified three 22q11.2-linked genes involved in known and previously undescribed pathways orchestrating neuronal functions in vivo that explain approximately 40% of the transcriptional changes observed in a 22q11.2-deletion mouse model. Our findings suggest that the 22q11.2-deletion syndrome transcriptional phenotype found in mature neurons may in part be due to the broad dysregulation of a class of genes associated with disease susceptibility that are important for dysfunctional RNA processing and synaptic function. Our study establishes a flexible and scalable direct in vivo method to facilitate causal understanding of biological and disease mechanisms with potential applications to identify genetic interventions and therapeutic targets for treating disease.

A Novel Interaction between MFN2/Marf and MARK4/PAR-1 Is Implicated in Synaptic Defects and Mitochondrial Dysfunction.

As cellular energy powerhouses, mitochondria undergo constant fission and fusion to maintain functional homeostasis. The conserved dynamin-like GTPase, Mitofusin2 (MFN2)/mitochondrial assembly regulatory factor (Marf), plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, is not clearly understood. Here, we identified a novel interaction between MFN2/Marf and microtubule affinity-regulating kinase 4 (MARK4)/PAR-1. In the Drosophila larval neuromuscular junction, muscle-specific overexpression of MFN2/Marf decreased the number of synaptic boutons, and the loss of MARK4/PAR-1 alleviated the synaptic defects of MFN2/Marf overexpression. Downregulation of MARK4/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2/Marf overexpression in the Drosophila muscles as well as in the cultured cells. In addition, knockdown of MARK4/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2/Marf overexpression in mammalian cells. Together, our results indicate that the interaction between MFN2/Marf and MARK4/PAR-1 is fine-tuned to maintain synaptic integrity and mitochondrial homeostasis, and its dysregulation may be implicated in neurologic pathogenesis.

Nanoscale reorganisation of synaptic proteins in Alzheimer's disease.

AIMS: Synaptic strength depends strongly on the subsynaptic organisation of presynaptic transmitter release and postsynaptic receptor densities, and their alterations are expected to underlie pathologies. Although synaptic dysfunctions are common pathogenic traits of Alzheimer's disease (AD), it remains unknown whether synaptic protein nano-organisation is altered in AD. Here, we systematically characterised the alterations in the subsynaptic organisation in cellular and mouse models of AD. METHODS: We used immunostaining and super-resolution stochastic optical reconstruction microscopy imaging to quantitatively examine the synaptic protein nano-organisation in both Aß1-42-treated neuronal cultures and cortical sections from a mouse model of AD, APP23 mice. RESULTS: We found that Aß1-42-treatment of cultured hippocampal neurons decreased the synaptic retention of postsynaptic scaffolds and receptors and disrupted their nanoscale alignment to presynaptic transmitter release sites. In cortical sections, we found that while GluA1 receptors in wild-type mice were organised in subsynaptic nanoclusters with high local densities, receptors in APP23 mice distributed more homogeneously within synapses. This reorganisation, together with the reduced overall receptor density, led to reduced glutamatergic synaptic transmission. Meanwhile, the transsynaptic alignment between presynaptic release-guiding RIM1/2 and postsynaptic scaffolding protein PSD-95 was reduced in APP23 mice. Importantly, these reorganisations were progressive with age and were more pronounced in synapses in close vicinity of Aß plaques with dense cores. CONCLUSIONS: Our study revealed a spatiotemporal-specific reorganisation of synaptic nanostructures in AD and identifies dense-core amyloid plaques as the major local inductor in APP23 mice.

N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection.

Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIß (CaMKIIß). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIß, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.

Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.

BACKGROUND: A consensus has formed that neural circuits in the brain underlie the pathogenesis of temporal lobe epilepsy (TLE). In particular, the synaptic excitation/inhibition balance (E/I balance) has been implicated in shifting towards elevated excitation during the development of TLE. METHODS: Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to generate a model of TLE. Next, electroencephalography (EEG) recording was applied to verify the stability and detectability of spontaneous recurrent seizures (SRS) in rats. Moreover, hippocampal slices from rats and patients with mesial temporal lobe epilepsy (mTLE) were assessed using immunofluorescence to determine the alterations of excitatory and inhibitory synapses and microglial phagocytosis. RESULTS: We found that KA induced stable SRSs 14 days after status epilepticus (SE) onset. Furthermore, we discovered a continuous increase in excitatory synapses during epileptogenesis, where the total area of vesicular glutamate transporter 1 (vGluT1) rose considerably in the stratum radiatum (SR) of cornu ammonis 1 (CA1), the stratum lucidum (SL) of CA3, and the polymorphic layer (PML) of the dentate gyrus (DG). In contrast, inhibitory synapses decreased significantly, with the total area of glutamate decarboxylase 65 (GAD65) in the SL and PML diminishing enormously. Moreover, microglia conducted active synaptic phagocytosis after the formation of SRSs, especially in the SL and PML. Finally, microglia preferentially pruned inhibitory synapses during recurrent seizures in both rat and human hippocampal slices, which contributed to the synaptic alteration in hippocampal subregions. CONCLUSIONS: Our findings elaborately characterize the alteration of neural circuits and demonstrate the selectivity of synaptic phagocytosis mediated by microglia in TLE, which could strengthen the comprehension of the pathogenesis of TLE and inspire potential therapeutic targets for epilepsy treatment.

Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis.

Recent evidence has supported the hypothesis that amyotrophic lateral sclerosis (ALS) is a multi-step disease, as the onset of symptoms occurs after sequential exposure to a defined number of risk factors. Despite the lack of precise identification of these disease determinants, it is known that genetic mutations may contribute to one or more of the steps leading to ALS onset, the remaining being linked to environmental factors and lifestyle. It also appears evident that compensatory plastic changes taking place at all levels of the nervous system during ALS etiopathogenesis may likely counteract the functional effects of neurodegeneration and affect the timing of disease onset and progression. Functional and structural events of synaptic plasticity probably represent the main mechanisms underlying this adaptive capability, causing a significant, although partial and transient, resiliency of the nervous system affected by a neurodegenerative disease. On the other hand, the failure of synaptic functions and plasticity may be part of the pathological process. The aim of this review was to summarize what it is known today about the controversial involvement of synapses in ALS etiopathogenesis, and an analysis of the literature, although not exhaustive, confirmed that synaptic dysfunction is an early pathogenetic process in ALS. Moreover, it appears that adequate modulation of structural and functional synaptic plasticity may likely support function sparing and delay disease progression.

Time-dependent and selective microglia-mediated removal of spinal synapses in neuropathic pain.

Neuropathic pain is a debilitating condition resulting from damage to the nervous system. Imbalance of spinal excitation and inhibition has been proposed to contribute to neuropathic pain. However, the structural basis of this imbalance remains unknown. Using a preclinical model of neuropathic pain, we show that microglia selectively engulf spinal synapses that are formed by central neurons and spare those of peripheral sensory neurons. Furthermore, we reveal that removal of inhibitory and excitatory synapses exhibits distinct temporal patterns, in which microglia-mediated inhibitory synapse removal precedes excitatory synapse removal. We also find selective and gradual increase in complement depositions on dorsal horn synapses that corresponds to the temporal pattern of microglial synapse pruning activity and type-specific synapse loss. Together, these results define a specific role for microglia in the progression of neuropathic pain pathogenesis and implicate these immune cells in structural remodeling of dorsal horn circuitry.

Involvement of miR-135a-5p Downregulation in Acute and Chronic Stress Response in the Prefrontal Cortex of Rats.

Stress is a key risk factor in the onset of neuropsychiatric disorders. The study of the mechanisms underlying stress response is important to understand the etiopathogenetic mechanisms and identify new putative therapeutic targets. In this context, microRNAs (miRNAs) have emerged as key regulators of the complex patterns of gene/protein expression changes in the brain, where they have a crucial role in the regulation of neuroplasticity, neurogenesis, and neuronal differentiation. Among them, miR-135a-5p has been associated with stress response, synaptic plasticity, and the antidepressant effect in different brain areas. Here, we used acute unavoidable foot-shock stress (FS) and chronic mild stress (CMS) on male rats to study whether miR-135a-5p was involved in stress-induced changes in the prefrontal cortex (PFC). Both acute and chronic stress decreased miR-135a-5p levels in the PFC, although after CMS the reduction was induced only in animals vulnerable to CMS, according to a sucrose preference test. MiR-135a-5p downregulation in the primary neurons reduced dendritic spine density, while its overexpression exerted the opposite effect. Two bioinformatically predicted target genes, Kif5c and Cplx1/2, were increased in FS rats 24 h after stress. Altogether, we found that miR-135a-5p might play a role in stress response in PFC involving synaptic mechanisms.

Fc effector of anti-Aß antibody induces synapse loss and cognitive deficits in Alzheimer's disease-like mouse model.

Passive immunotherapy is one of the most promising interventions for Alzheimer's disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aß-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aß, antibody, and complement. Notably, anti-Aß antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aß-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aß-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.

Amyloid precursor protein 𝛽CTF accumulates in synapses in sporadic and genetic forms of Alzheimer's disease.

AIMS: Amyloid precursor protein (APP) 𝛽-C-terminal fragment (𝛽CTF) may have a neurotoxic role in Alzheimer's disease (AD). 𝛽CTF accumulates in the brains of patients with sporadic (SAD) and genetic forms of AD. Synapses degenerate early during the pathogenesis of AD. We studied whether the 𝛽CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS). METHODS: We used array tomography to determine APP at synapses in human AD tissue. We measured 𝛽CTF, A𝛽40, A𝛽42 and phosphorylated tau181 (p-tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls. RESULTS: APP colocalised with pre- and post-synaptic markers in human AD brains. APP 𝛽CTF was enriched in AD synaptosomes. CONCLUSIONS: We demonstrate that 𝛽CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for 𝛽CTF in synapse degeneration. Therapies aimed at mitigating 𝛽CTF accumulation could be potentially beneficial in AD.

Synaptic resilience is associated with maintained cognition during ageing.

INTRODUCTION: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. METHODS: We examined post-mortem brain tissue from people in mid-life (n = 15), healthy ageing with either maintained cognition (n = 9) or lifetime cognitive decline (n = 8), and Alzheimer's disease (n = 13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer's brain homogenate. RESULTS: Synaptic pathology increased, and expression of genes involved in synaptic signaling decreased between mid-life, healthy ageing and Alzheimer's. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signaling genes compared to people with cognitive decline. DISCUSSION: Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.

Synaptic degeneration in Alzheimer disease.

Alzheimer disease (AD) is characterized by progressive cognitive decline in older individuals accompanied by the presence of two pathological protein aggregates - amyloid-ß and phosphorylated tau - in the brain. The disease results in brain atrophy caused by neuronal loss and synapse degeneration. Synaptic loss strongly correlates with cognitive decline in both humans and animal models of AD. Indeed, evidence suggests that soluble forms of amyloid-ß and tau can cause synaptotoxicity and spread through neural circuits. These pathological changes are accompanied by an altered phenotype in the glial cells of the brain - one hypothesis is that glia excessively ingest synapses and modulate the trans-synaptic spread of pathology. To date, effective therapies for the treatment or prevention of AD are lacking, but understanding how synaptic degeneration occurs will be essential for the development of new interventions. Here, we highlight the mechanisms through which synapses degenerate in the AD brain, and discuss key questions that still need to be answered. We also cover the ways in which our understanding of the mechanisms of synaptic degeneration is leading to new therapeutic approaches for AD.