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Whole organism snRNA-seq reveals systemic peripheral changes in Alzheimer’s Disease fly models

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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE261656 | GEO | 2024/03/14

REPOSITORIES: GEO

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Project description:Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease(AD), which is closely related to tau pathology and hippocampal impairment. Given the heterogeneity of brain neurons, the precise role of different brain neurons in terms of their sensitivity to tau accumulation and contribution to AD-like social memory loss remains unclear and requires further investigation. Methods: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic experiments, social behavioral test, hippocampal electrophysiology, immunofluorescent staining and in vivo optical fiber recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine their effects on social memory in mice. Results: By proteomic and phosphoproteomic analyses, we identified the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, not dorsal CA1 (dCA1), but vCA1, especially its excitatory and PV neurons, were fully filled with mislocated and phosphorylated tau. Overexpression of human Tau (hTau) in excitatory and PV neurons respectively mimicked AD-like tau accumulation, significantly inhibited the neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythm and time-window efficiently ameliorated tau-impaired social memory. Significantly, one-month administration of UA efficiently decreased tau accumulation via autophagy in a TFEB (transcription factor EB)-dependent manner and recovered vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1, and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for AD treatment in the future.

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Whole organism snRNA-seq reveals systemic peripheral changes in Alzheimer’s Disease fly models

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