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Obesity escalates Alzheimer’s disease and cancer via excess phosphatidylethanolamine-driven membrane remodeling

ABSTRACT: The paradox of Alzheimer’s disease (AD) and cancer refers to the asynchronism of the two diseases. Understanding the correlation between cancer and AD could enhance research efficiency by consolidating efforts, lead to broader therapeutic impacts through drugs targeting shared mechanisms. Obesity is believed to synchronize this dichotomy by coordinating the onset and progression of both AD and cancer, although the precise mechanism remains unclear. In this study, leveraging integrated multi-modality data, including lipidomics, proteomics, bulk and single-cell RNA transcriptomics, drug repositioning and subcellular visualization, we identified that an overabundance of phosphatidylethanolamine (PEhigh) flux from white adipose tissue in obese individuals underlies this agonist role, driving lipid droplet accumulation and disrupting lipid homeostasis. PEhigh flux escalates both cancer and AD by potentiating immune evasion in tumor models and facilitating amyloidosis and tauopathies in AD models, while restoring PE homeostasis in the brain alleviates cognitive impairment. Mechanistically, our validation demonstrates that PEhigh flux induces autophagic, immunological, and membrane remodeling processes, driving T-cell and microglia dysfunction, spatiotemporal disruption of intracellular signaling, and destabilization of critical membrane structures. The potentially convergent mechanisms and divergent details of PE across AD and cancer highlight its multifaceted implications and the druggability of the associated signaling pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE280474 | GEO | 2024/11/08

REPOSITORIES: GEO

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