Transcriptomics

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An aging-sensitive compensatory neuroprotective factor that confers cognitive resilience


ABSTRACT: Endogenous compensatory changes influence trajectory of brain aging, cognitive decline and Alzheimer’s Disease (AD) risk, however, the identities of underlying mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated synapse loss, emergence of inflammatory microglia, reactive astrogliosis, lipid dysregulation and memory impairment. Boosting Pla2g2f in DGCs during aging prevents these pathophysiological impairments and modifies trajectory of cognitive decline. In human microglia-neuron coculture experiments PLA2G2F mediates intercellular signaling to decrease lipid burden. Boosting Pla2g2f expression in an aging-sensitive AD model reduces amyloid load and preserves memory. Thus, PLA2G2F functions as a compensatory neuroprotective factor that counteracts aging-associated cognitive decline.

ORGANISM(S): Mus musculus

PROVIDER: GSE261906 | GEO | 2026/08/10

REPOSITORIES: GEO

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