An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience

 Sounds like your doctor should completely understand this so your cognitive resilience can be built up again to prevent dementia. At least if you have a competent doctor! Do you have a competent? doctor?

An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience

Amar Sahay¹

ORCID

Email

Cinzia Vicidomini²

Travis Goode³

ORCID

Kathleen McAvoy¹

Ruilin Yu⁴

ORCID

Conor Beveridge⁴

Sanjay Iyer⁴

Matheus Victor⁵

Noelle Leary⁵

Michael Steinbaugh³

ORCID

Zon Lai⁶

Marina Lyon⁷

Manuel Silvestre⁷

Gracia Bonilla⁷

Ruslan Sadreyev⁸

Tobias Walther⁹

Shannan Sui¹⁰

Takaomi Saido¹¹

ORCID

Kei Yamamoto¹²

Makoto Murakami¹³

Li-Huei Tsai⁵

ORCID

Gaurav Chopra¹⁴

ORCID

Liam Evans⁷

¹ Massachusetts General Hospital & Harvard Medical School,

² CNR Neuroscience Insitute,

³ Harvard University,

⁴ Purdue University,

⁵ Massachusetts Institute of Technology,

⁶ Harvard Chan Advanced Multi-omics Platform, Harvard T.H. Chan School of Public Health,

⁷ MGH and HMS,

⁸ Massachusetts General Hospital/ Harvard Medical School,

⁹ MSKCC,

¹⁰ Harvard Chan Bioinformatics Core, Harvard School of Public Health,

¹¹ RIKEN Center for Brain Science,

¹² Tokushima University,

¹³ Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science,

¹⁴ Purdue University West Lafayette

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https://doi.org/10.21203/rs.3.rs-4920738/v1

This work is licensed under a CC BY 4.0 License

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.