
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

39211220
10.1101/2024.07.26.605338
preprint
2
Article
An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience
Vicidomini Cinzia
Goode Travis D. http://orcid.org/0000-0003-1432-8894

McAvoy Kathleen M.
Yu Ruilin
Beveridge Conor H.
Iyer Sanjay N.
Victor Matheus B.
Leary Noelle
Evans Liam
Steinbaugh Michael J.
Lai Zon Weng
Lyon Marina C.
Silvestre Manuel Rico F.S
Bonilla Gracia
Sadreyev Ruslan I.
Walther Tobias C.
Sui Shannan Ho
Saido Takaomi http://orcid.org/0000-0003-1970-6903

Yamamoto Kei
Murakami Makoto
Tsai Li-Huei http://orcid.org/0000-0003-1262-0592

Chopra Gaurav
Sahay Amar
03 9 2024
2024.07.26.605338https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.07.26.605338
nihpp-2024.07.26.605338.pdf
Abstract

Breakdown of lipid homeostasis is thought to contribute to pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimer’s Disease (AD). Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in preserving neuronal circuit functions, staving off cognitive decline, and mitigating risk for AD. However, the identities of such 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 pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that maintains lipid homeostasis to counteract aging-associated cognitive decline.
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