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DP1 Receptor Blockade Attenuates Microglial Senescence and Cognitive Decline Caused by PTGDS in Exosomes From Aged

Yaru Liu1,2, Pan Liao2,3, Bo Yan1,2

  • 1Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.

Aging Cell
|September 20, 2025
PubMed

Insights

Brain exosomes from aged mice drive cognitive decline by activating microglia and promoting senescence. Blocking the DP1 receptor reverses these effects, offering a potential therapeutic target for aging-related neuroinflammation and cognitive impairment.

Area of Science:

  • Neuroscience
  • Immunology
  • Aging Research

Background:

  • Aging is linked to neurodegenerative diseases and cognitive decline.
  • Chronic low-grade brain inflammation, driven by microglial activation, underlies these conditions.
  • The precise mechanisms by which aged brain exosomes impact microglial function and senescence are not fully understood.

Purpose of the Study:

  • To investigate whether brain-derived exosomes from aged mice induce pro-inflammatory states and cellular senescence in microglia.
  • To elucidate the molecular pathways involved in exosome-mediated microglial dysfunction.
  • To explore the therapeutic potential of targeting these pathways for age-related cognitive decline.

Main Methods:

  • Administration of aged mouse brain-derived exosomes (A-exo) to young mice.
  • Analysis of microglial activation, lipid droplet accumulation, and senescence-associated secretory phenotype (SASP) secretion.
  • Assessment of PTGDS expression, PGD2 levels, and DP1 receptor signaling.
  • Pharmacological blockade of the DP1 receptor in both young and aged mice.

Main Results:

  • A-exo induced cognitive decline, microglial overactivation, lipid droplet accumulation, and SASP secretion in young mice.
  • Elevated PTGDS in A-exo increased PGD2 levels, leading to sustained DP1 signaling.
  • DP1 receptor blockade ameliorated A-exo-induced microglial changes, myeloid cell infiltration, and senescence.
  • DP1 receptor blockade improved cognitive function, neuroinflammation, and senescence in aged mice.

Conclusions:

  • Brain-derived exosomes from aged mice promote microglial senescence and neuroinflammation, contributing to cognitive decline.
  • Sustained DP1 signaling, driven by elevated PTGDS in A-exo, is a key mechanism.
  • Targeting the DP1 receptor represents a promising therapeutic strategy for age-related cognitive dysfunction and neuroinflammation.
Keywords:
DP1 receptorsagingexosomesmicroglianeuroinflammation

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