SEARCH · bioRxiv Science

Results for “Pathology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources

bioRxiv2023

Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice

TMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice. Moreover, Tmem106b-/- PS19 mice develop significantly increased disruption of the neuronal cytoskeleton, autophagy-lysosomal function, and lysosomal trafficking along the axon as well as enhanced gliosis compared with PS19 and Tmem106b-/- mice. Together, our findings demonstrate that loss of TMEM106B drastically exacerbates Tau pathology and its associated disease phenotypes, and provide new insights into the roles of TMEM106B in neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Dynamic neuroinflammatory profiles predict Alzheimer's disease pathology in microglia-containing cerebral organoids

Neuroinflammation and the underlying dysregulated immune responses of microglia actively contribute to the progression and, likely, the initiation of Alzheimers disease (AD). Fine-tuned therapeutic modulation of immune dysfunction to ameliorate disease cannot be achieved without the characterization of diverse microglial states that initiate unique, and sometimes contradictory, immune responses that evolve over time in chronic inflammatory environments. Because of the functional differences between human and murine microglia, untangling distinct, disease-relevant reactive states and their corresponding effects on pathology or neuronal health may not be possible without the use of human cells. In order to profile shifting microglial states in early AD and identify microglia-specific drivers of disease, we differentiated human induced pluripotent stem cells (iPSCs) carrying a familial AD PSEN2 mutation or its isogenic control into cerebral organoids and quantified the changes in cytokine concentrations over time with Luminex XMAP technology. We used partial least squares (PLS) modeling to build cytokine signatures predictive of disease and age to identify key differential patterns of cytokine expression that inform the overall organoid immune milieu and quantified the corresponding changes in protein pathology. AD organoids exhibited an overall reduction in cytokine secretion after an initial amplified immune response. We demonstrate that reduced synapse density observed in the AD organoids is prevented with microglial depletion. Crucially, these differential effects of dysregulated immune signaling occurred without the accumulation of pathological proteins. In this study, we used microglia-containing AD organoids to quantitatively characterize an evolving immune milieu, made up of a diverse of collection of activation patterns and immune responses, to identify how a dynamic, overall neuroinflammatory state negatively impacts neuronal health and the cell-specific contribution of microglia.

neuroscience↗

bioRxiv2023

A human immune/muscle xenograft model of FSHD muscle pathology

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) disease progression is associated with muscle inflammation, although its role in FSHD muscle pathology is unknown. MethodsWe have developed a novel humanized mouse strain, NSG-SGM3-W41, that supports the co- engraftment of human hematopoietic stem cells (HSCs) and muscle myoblasts as an experimental model to investigate the role of innate immunity in FSHD muscle pathology. ResultsThe NSG-SGM3-W41 mouse supports the selective expansion of human innate immune cell lineages following engraftment of human HSCs and the co-engraftment and differentiation of patient-derived FSHD or control muscle myoblasts. Immunohistological and NanoString RNA expression assays establish that muscle xenografts from three FSHD subjects were immunogenic compared to those from unaffected first-degree relatives. FSHD muscle xenografts preferentially accumulated human macrophages and B cells and expressed early complement genes of the classical and alternative pathways including complement factor C3 protein, which is a mediator of early complement function through opsonization to mark damaged cells for macrophage engulfment. FSHD muscle xenografts also underwent immune donor dependent muscle turnover as assayed by human spectrin {beta}1 immunostaining of muscle fibers and by NanoString RNA expression assays of muscle differentiation genes. ConclusionsThe NSG-SGM3-W41 mouse provides an experimental model to investigate the role of innate immunity and complement in FSHD muscle pathology and to develop FSHD therapeutics targeting DUX4 and the innate immunity inflammatory responses.

immunology↗

bioRxiv2023

Three-dimensional histology reveals dissociable human hippocampal long axis gradients of Alzheimer's pathology

INTRODUCTIONThree-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without an MRI reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimers Disease. METHODSBlockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space. RESULTSPath2MR successfully registered histological sections to their anatomical position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, while amyloid-{beta} displayed a quadratic anterior-posterior distribution. CONCLUSIONPath2MR, which enables 3D histology using any brain bank dataset, revealed significant differences along the hippocampus between tau and amyloid-{beta}.

neuroscience↗

bioRxiv2023

Modulation of Alzheimer's Disease Brain Pathology in Mice by Gut Bacterial Deletion: The Role of Il-17a and Microglial MyD88

Gut bacteria regulate brain pathology of Alzheimers disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene, or haploinsufficiency of MyD88 in microglia were treated with antibiotics-supplemented or normal drinking water for 2 months. Antibiotic treatment eradicated gut bacteria, particularly in the phyla Bacteroidetes and Firmicutes, and reduced Il-17a-expressing CD4-positive T lymphocytes. Deletion of gut bacteria inhibited inflammatory activation in the brain and microglia, and reduced cerebral A{beta} levels in APP-transgenic mice, which was abolished by deficiency of Il-17a or haploinsufficiency of MyD88 in microglia. As possible mechanisms regulating A{beta} pathology, deletion of gut bacteria inhibited {beta}-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, deletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a and microglial MyD88-involved signalling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology.

neuroscience↗

bioRxiv2024

Disease-associated astrocyte epigenetic memory promotes CNS pathology

Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE)1-8. However, little is known about the stability of these disease-associated astrocyte subsets, their regulation, and whether they integrate past stimulation events to respond to subsequent challenges. Here, we describe the identification of an epigenetically controlled memory astrocyte subset which exhibits exacerbated pro-inflammatory responses upon re-challenge. Specifically, using a combination of single-cell RNA sequencing (scRNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), and cell-specific in vivo CRISPR/Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) used by the histone acetyltransferase p300 to control chromatin accessibility. ACLY+p300+ memory astrocytes are increased in acute and chronic EAE models; the genetic targeting of ACLY+ p300+ astrocytes using CRISPR/Cas9 ameliorated EAE. We also detected responses consistent with a pro-inflammatory memory phenotype in human astrocytes in vitro; scRNA-seq and immunohistochemistry studies detected increased ACLY+ p300+ astrocytes in chronic MS lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, MS. These findings may guide novel therapeutic approaches for MS and other neurologic diseases.

immunology↗

bioRxiv2024

The long distance relationship of regional amyloid burden and tau pathology spread

IntroductionConsistent with the amyloid-cascade-hypothesis, we tested whether regional amyloid burden is associated with tau pathology increases in spatially independent brain regions and whether functional connectivity serves as a mediator bridging the observed spatial gap between these pathologies. MethodsData of 98 amyloid-positive and 35 amyloid-negative subjects with baseline amyloid (18F-AV45) and longitudinal tau (18F-AV1451) PET were selected from ADNI. Annual tau change maps were computed. All images were z-transformed using the amyloid-negative subjects as reference. Z-maps of baseline amyloid and annual tau change were submitted to a parallel independent component analysis in GIFT, yielding six component pairs linking spatial patterns of baseline amyloid to longitudinal tau increase. Next, we used the region of maximum coefficient per component as seeds for functional connectivity analyses in a healthy control dataset. This resulted in six pairs of amyloid and tau seed-based networks (SBN). The spatial overlap between these SBNs and components (amyloid OR tau change) and the combined component pairs (amyloid AND tau change) were quantified. ResultsAmyloid SBNs presented greater spatial overlap with their respective amyloid components (24%-54%) than tau SBNs with the respective tau change components (16%-40%). However, the spatial combination of amyloid and tau component pairs showed highest spatial overlap with the amyloid SBNs (up to 62% vs. 39% for the tau SBNs). ConclusionMechanistically, regional associations of amyloid and tau pathology may be driven by underlying large-scale functional networks. Functional connections may thereby transmit soluble amyloid to remote brain regions within the same network, likely triggering tau aggregation.

neuroscience↗

bioRxiv2024

Exploring social modulation: Microglia as a key mediator of individual immune response, plasticity and pathology in App-NL-G-F mouse model of Alzheimer's disease

This study explores the influence of lifestyle on Alzheimers disease (AD) progression using App-NL-G-F mice in a complex enrichment system. Mice exhibited social deficits before plaque pathology or memory impairment, revealing a crucial link between lifestyle, behavior, and neuroinflammation. Plasma analysis indicates early inflammation and apoptosis-related changes, setting the stage for identifying markers predicting plaque manifestation. Beyond pathology, social behavior is linked to adult neurogenesis and microglia coverage, forming a dynamic connection with microglia activation. Further, sc-RNA sequencing unveiled a decrease in interferon-responsive microglia and alteration in antigen processing with enrichment. These findings underscore the beneficial impact of social housing on microglia and interconnected factors, pointing to microglia as a critical mediator of the behavior-pathology-plasticity interplay in AD. The study enhances our understanding of AD complexity and offers insights into potential therapeutic strategies, emphasizing the multifaceted nature of AD progression and the role of lifestyle in shaping its course.

neuroscience↗

bioRxiv2024

Cerebrovascular pathology mediates associations between hypoxemia during rapid eye movement sleep and medial temporal lobe structure and function in older adults

Obstructive sleep apnea (OSA) is common in older adults and is associated with medial temporal lobe (MTL) degeneration and memory decline in aging and Alzheimers disease (AD). However, the underlying mechanisms linking OSA to MTL degeneration and impaired memory remains unclear. By combining magnetic resonance imaging (MRI) assessments of cerebrovascular pathology and MTL structure with clinical polysomnography and assessment of overnight emotional memory retention in older adults at risk for AD, cerebrovascular pathology in fronto-parietal brain regions was shown to statistically mediate the relationship between OSA-related hypoxemia, particularly during rapid eye movement (REM) sleep, and entorhinal cortical thickness. Reduced entorhinal cortical thickness was, in turn, associated with impaired overnight retention in mnemonic discrimination ability across emotional valences for high similarity lures. These findings identify cerebrovascular pathology as a contributing mechanism linking hypoxemia to MTL degeneration and impaired sleep-dependent memory in older adults.

neuroscience↗

bioRxiv2024

Mitochondrial bioenergetics stimulates autophagy for pathological tau clearance in tauopathy neurons

Hyperphosphorylation and aggregation of microtubule-associated tau is a pathogenic hallmark of tauopathies and a defining feature of Alzheimers disease (AD). Pathological tau is targeted by autophagy for clearance, but autophagy dysfunction is indicated in tauopathy. While mitochondrial bioenergetic failure has been shown to precede the development of tau pathology, it is unclear whether energy metabolism deficiency is involved in tauopathy-related autophagy defects. Here, we reveal that stimulation of anaplerotic metabolism restores defective oxidative phosphorylation (OXPHOS) in tauopathy which, strikingly, leads to enhanced autophagy and pronounced tau clearance. OXPHOS-induced autophagy is attributed to increased ATP-dependent phosphatidylethanolamine biosynthesis in mitochondria. Excitingly, early bioenergetic stimulation boosts autophagy activity and reduces tau pathology, thereby counteracting memory impairment in tauopathy mice. Taken together, our study sheds light on a pivotal role of bioenergetic dysfunction in tauopathy-linked autophagy defects and suggests a new therapeutic strategy to prevent toxic tau buildup in AD and other tauopathies.

neuroscience↗

bioRxiv2024

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

In Alzheimers disease, it is theorised that amyloid beta (A{beta}) and tau pathology contribute to synapse loss. However, there is limited information on how endogenous levels of tau and A{beta} protein relate to patient characteristics, or how manipulating physiological levels of A{beta} impacts synapses, in living adult, human brain. Here, we employed live human brain slice cultures as a translational tool to assess endogenous tau and A{beta} release, pathology, and response to experimental manipulation. We found that the levels of A{beta}1-40 and tau detected in the culture medium depend on donor age, and brain region, respectively. Pharmacologically raising physiological A{beta} concentration enhanced levels of synaptic transcripts. Treatment of slices with A{beta}-containing Alzheimers disease brain extract resulted in postsynaptic A{beta} uptake and loss of presynaptic puncta. These data indicate that physiological and pathological A{beta} can have opposing effects on synapses in living human brain tissue.

neuroscience↗

bioRxiv2024

C9orf72 poly-PR condensation induces nuclear TDP-43 pathology and is inhibited by RNA in an optogenetic cell model

Proteinaceous inclusions formed by C9orf72 derived dipeptide-repeat (DPR) proteins are a histopathological hallmark in ~50% of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) cases. However DPR aggregation/inclusion formation could not be efficiently recapitulated in cell models for four out of five DPRs. In this study, using optogenetics, we achieved chemical-free poly-PR condensation/aggregation in cultured cells, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-centre appearance, resembling anisosomes formed by aberrant TDP-43 species, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without the activation of stress response. Cytoplasmic poly-PR aggregates that formed under prolonged light stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Our data suggest that poly-PR anisotropic condensation in the nucleus, causative of nuclear TDP-43 dysfunction, may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates may represent a more common cellular pathology in neurodegeneration than previously thought. Highlights- Optogenetics can be used to model C9orf72 DPR condensation in cultured cells. - Opto-PR forms hollow nuclear condensates, and RNA limits their growth by fusion. - Opto-PR condensation leads to stress-independent TDP-43 pathology in the nucleus. - Cytoplasmic poly-PR assemblies are persistent and selectively sequester TDP-43. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/581933v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@ccce86org.highwire.dtl.DTLVardef@ae2b3org.highwire.dtl.DTLVardef@a9880eorg.highwire.dtl.DTLVardef@236c32_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches

The thymus, a central primary lymphoid organ of the immune system, plays a key role in T cell development. Surprisingly, the thymus is quite neglected with regards to standardized pathology approaches and practices for assessing structure and function. Most studies use multispectral flow cytometry to define the dynamic composition of the thymus at the cell population level, but they are limited by lack of contextual insight. This knowledge gap hinders our understanding of various thymic conditions and pathologies, particularly how they affect thymic architecture, and subsequently, immune competence. Here, we introduce a digital pathology pipeline to address these challenges. Our approach can be coupled to analytical algorithms and utilizes rationalized morphometric assessments of thymic tissue, ranging from tissue-wide down to microanatomical and ultrastructural levels. This pipeline enables the quantitative assessment of putative changes and adaptations of thymic structure to stimuli, offering valuable insights into the pathophysiology of thymic disorders. This versatile pipeline can be applied to a wide range of conditions that may directly or indirectly affect thymic structure, ranging from various cytotoxic stimuli inducing acute thymic involution to autoimmune diseases, such as myasthenia gravis. Here, we demonstrate applicability of the method in a mouse model of age-dependent thymic involution, both by confirming established knowledge, and by providing novel insights on intrathymic remodeling in the aged thymus. Our orthogonal pipeline, with its high versatility and depth of analysis, promises to be a valuable and practical toolset for both basic and translational immunology laboratories investigating thymic function and disease.

immunology↗

bioRxiv2024

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression.

Alzheimers disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimers disease onset and progression. Characterizing the initial phase of Alzheimers disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimers disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis-and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory networks functionality. These results suggest that the early loss of microglia could be a pivotal event in the progression of Alzheimers disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

neuroscience↗

bioRxiv2024

Post-mortem evidence for a reciprocal relationship between genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies.

DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications on cellular physiology, including in proteostasis, and have been recently implicated in many neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been implicated in DNA double strand break (DSB) repair function. Consistently, DSB induction has been demonstrated in cell and animal models of synucleinopathy. Nevertheless, the types of DNA damage and the contribution of DNA damage towards Lewy body (LB) formation in synucleinopathies are unknown. Here, we demonstrate the increase of DSB in neuronal and non-neuronal cellular populations of post-mortem temporal cortex tissue from dementia with Lewy body (DLB) patients and demonstrate increases in DSBs early at a presymptomatic age of aSyn transgenic mice. Strikingly, in postmortem DLB tissue, DNA damage-derived ectopic cytoplasmic genomic material (eCGM) was evident within the majority of LBs examined. The observed cellular pathology was consistent with nucleoproteasomal upregulation of associated DNA damage repair proteins, particularly in base excision repair and DSB repair pathways. Collectively our study demonstrates the early occurrence of DNA damage and associated nucleoproteasomal changes in response to nuclear aSyn pathology. Furthermore, the data suggests a potential involvement for DNA damage derived eCGM for the facilitation of cytoplasmic aSyn aggregates. Ultimately, uncovering pathological mechanisms underlying DNA damage in DLB sheds light into novel disease mechanisms and opens novel possibilities for diagnosing and treating synucleinopathies.

neuroscience↗

bioRxiv2024

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the specific molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse ApoE with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, the R136S mutation reduced interferon response to tau pathology in both mouse and human microglia, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with a cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, suppression of microglial cGAS-STING-IFN pathway plays a central role in mediating the protective effects of R136S against tauopathy. One-sentence summaryThe R136S mutation on APOE3 enhances resistance to tau-related pathology and toxicity by downregulating the cGAS-STING-IFN signaling pathway.

neuroscience↗

bioRxiv2024

Corticosteroids prevent pathological angiogenesis yet compromise reparative vascular remodeling in the retina

Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system (CNS), this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Here we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that broad spectrum corticosteroid drugs such as dexamethasone suppress initial formation of pathological pre-retinal neovascularization in early stages of disease, yet blunt successive waves of reparative inflammation and hence prevent beneficial vascular remodeling. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1 (CX3CR1)-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing Lyz-M (lysozyme 2) are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered when treating retinal vascular disease and particularly in stages associated with persistent neovascularization.

immunology↗

bioRxiv2024

Troriluzole Rescues Glutamatergic Deficits, Amyloid and Tau Pathology, and Synaptic and Memory Impairments in 3xTg-AD Mice

Alzheimers disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (A{beta}) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in A{beta} models, suggesting the changes in pool size may be due to A{beta} and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimers disease.

pharmacology and toxicology↗