ABSTRACT: Alzheimer's Disease (AD) is known for its profound impact on the brain, yet its systemic effects, particularly on peripheral tissues, remain underexplored. To address this gap, we utilized Drosophila, an established model for aging and neurodegeneration studies, to create the Alzheimer's Disease Fly Cell Atlas (AD-FCA). This comprehensive atlas comprises whole-organism single-nucleus transcriptomes from 219 cell types in two AD models, where adult flies express human Aβ42 or Tau exclusively in neurons. Our in-depth analyses reveal that Aβ42 prominently affects peripheral sensory neurons, whereas Tau expression leads to notable alterations in several non-neuronal tissues, including the gut, fat body, and reproductive system. The AD-FCA uncovers the nuanced interplay between neuronal pathology and peripheral tissue responses, offering novel insights into potential biomarkers and the systemic nature of AD.
Project description:Deciphering the pathophysiological mechanisms that lead from the alteration of human Tau biology to neuronal death in tauopathies including Alzheimer's disease (AD), fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) depends notably on the identification of Tau cellular partners and a better understanding of Tau functions. In this aim, we performed gene expression profiling to identify upregulated and downregulated genes in response to ectopic induced expression for 3 days of human Tau0N4RWT protein in Drosophila primary neuronal cultures from Elav-GAL4GS larval brains.
Project description:Alzheimer's disease (AD), the most common neurodegenerative disorder caused by neuronal loss which results in memory loss. Formation of neurofibrillary tangles composed of abnormal hyper phosphorylation of tau protein is one of the major pathological hallmarks for AD. Several neurodegenerative disorders including AD are associated with abnormal protein phosphorylation events.
Project description:A persistent and non-resolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors.
Project description:Levels of blood exosomal Aβ42, total Tau (t-Tau) and phosphorylated Tau (p-Tau) had a high correlation with their concentrations in cerebrospinal fluid (CSF), demonstrating that exosomal biomarkers have equal contribution as those in CSF for the diagnosis of AD. We aimed to comprehensively characterize the proteome of plasma exosomes to identify differentially expressed proteins (DEPs) and pathways in AD. Tandem mass tag (TMT) labeled quantitative proteomics was applied to analyze plasma exosomal proteins in 9 AD patients and 9 healthy controls.
Project description:Neuroinflammation is one of the major neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia often co-exist in the same brain regions where tau protein accumulates as hyperphosphorylated and aggregated PHFs or neurofibrillary tangles (NFTs) within neurons in patients with AD and related tauopathies. However, the exact mechanisms how pathological tau could induce neuroinflammatory responses are not clear. In this study, we treated primary human microglia with purified human PHFs and performed RNA-sequence analysis.
Project description:Alzheimer's disease is the most common form of dementia characterized on cognitive impairment. Autophagy-lysosome dysfunction is linked to AD pathology. Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphorus flame retardants with the potential to induce neuronal damage. We found that TDCIPP significantly increased expression of BACE1 and of Aβ42. TMT labeled proteomic study were used to reveal profile changes of N2a-APPswe cells after exposure by TDCIPP. Proteomic and bioinformatic analysis revealed that lysosomal proteins were dysregulated after TDCIPP treatment in N2a-APPswe cells. LC3, P62, CTSD, and LAMP1 were increased, while STAT1 was decreased after TDCIPP exposure and dysregulated proteins were validated by Western blotting. Our results, for the first time revealed that TDCIPP could be one of potential environment risk factors for AD development. Autophagy dysregulation may take an important role on TDCIPP induced Aβ42 production.
Project description:FK506 binding protein 51kDa (FKBP51/FKBP5) is part of a mature heat shock protein 90kDa (Hsp90) chaperone complex that preserves tau. Microarray analysis of human brains reveal that FKBP51 gene expression selectively increased with age and Alzheimer's disease, which correlated with demethylation of the regulatory regions in the FKBP5 gene. Moreover, FKBP51 levels significantly correlated with Braak pathological staging. In addition, we show that in brains devoid of FKBP51, tau levels are reduced. Recombinant FKBP51 and Hsp90 synergize to block tau clearance through the proteasome and produce T22-positive tau oligomers. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved tau species, including phosphorylated and oligomeric tau that have been linked to Alzheimer's disease pathogenesis. FKBP51 blocked amyloid formation and decreased tangle load in the brain. These alterations in tau turnover and aggregate structure culminated in enhanced neurotoxicity. We propose a model where age-associated increases in FKBP51 levels can out-compete the association of other pro-degradation Hsp90 co-chaperones, resulting in neurotoxic tau accumulation. Thus, strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 could be therapeutically relevant for Alzheimer's disease and other tauopathies. These AD cases were processed simultaneously with the control cases (young and aged) included in GSE11882 Postmortem brain tissue was collected from ADRC brain banks. Cases were preferentially selected where 3 or more brain regions were available
Project description:Identifying factors underlying selective neuronal vulnerability is crucial for understanding Alzheimer's disease (AD) pathophysiology. The Neuromodulatory Subcortical System (NSS) includes nuclei that exhibit early, but varied vulnerability to tau accumulation and neuronal loss. This varied vulnerability represents a valuable opportunity to explore the underlying mechanisms of AD. In this study, we investigated factors contributing to selective neuronal vulnerability by comparing transcriptomic profiles of two similar NSS nuclei with differing vulnerabilities to AD, the locus coeruleus and substantia nigra. Using paired samples from well-characterized postmortem human tissue from individuals in early Braak stages and free of comorbid neuropathologic diagnoses, we identified pathways related to cholesterol homeostasis and antioxidant pathways response as key potential drivers of vulnerability.
Project description:Microbial infection, the strong trigger to directly induce inflammation in brain, is long considered a risk factor of Alzheimer's disease (AD), but how these infections contribute to neurodegeneration remains underexplored. To examine the effect of herpes simplex virus type 1 (HSV-1) infection on tauopathy in local hippocampus of P301S mice, we utilized a modified HSV-1 strain (mHSV-1) potentially relevant to AD, we found that its infection promotes tau-related pathology in part via activating neuroimmune cGAS-STING pathway in the tau mouse model. Specifically, Sting ablation causes the detectable improvement of neuronal dysfunction and loss in P301S mice, which is causally linked to lowered proinflammatory status in the brain. Administration of STING inhibitor H-151 alleviates neuroinflammation and tau-related pathology in P301S mice. These results jointly suggest that herpesviral infection, as the vital environmental risk factor, could induce tau-related pathology in AD pathogenesis partially via neuroinflammatory cGAS-STING pathway.
Project description:Microbial infection, the strong trigger to directly induce inflammation in brain, is long considered a risk factor of Alzheimer's disease (AD), but how these infections contribute to neurodegeneration remains underexplored. To examine the effect of herpes simplex virus type 1 (HSV-1) infection on tauopathy in local hippocampus of P301S mice, we utilized a modified HSV-1 strain (mHSV-1) potentially relevant to AD, we found that its infection promotes tau-related pathology in part via activating neuroimmune cGAS-STING pathway in the tau mouse model. Specifically, Sting ablation causes the detectable improvement of neuronal dysfunction and loss in P301S mice, which is causally linked to lowered proinflammatory status in the brain. Administration of STING inhibitor H-151 alleviates neuroinflammation and tau-related pathology in P301S mice. These results jointly suggest that herpesviral infection, as the vital environmental risk factor, could induce tau-related pathology in AD pathogenesis partially via neuroinflammatory cGAS-STING pathway.