Astrocyte Senescence Impairs Synaptogenesis due to Thrombospondin‐1 Loss

TL;DR

This study shows that aging astrocytes in the hippocampus lose their ability to support synapse formation due to reduced thrombospondin-1, and restoring it can reverse this effect.

Contribution

The paper identifies thrombospondin-1 loss in senescent astrocytes as a novel mechanism underlying age-related synaptic dysfunction.

Findings

Senescent astrocytes from SAMP8 mice show reduced synaptogenic function and thrombospondin-1 levels.

Adding thrombospondin-1 or overexpressing its gene in senescent astrocytes restores synaptogenesis.

Thrombospondin-1 and synaptic puncta are reduced in the hippocampus of SAMP8 mice.

Abstract

Cellular senescence is an irreversible state linked to aging that involves molecular and functional alterations. The mammalian hippocampus, a key brain region for learning and memory, is highly vulnerable to damage in age‐related neurodegenerative diseases, yet the role of cellular senescence in hippocampal aging remains underexplored. Here, we report an early onset of senescence signatures in hippocampal astrocytes of the accelerated aging and frailty mouse model SAMP8. We examine how astrocyte senescence affects excitatory synapse formation, focusing on soluble signals released by astrocytes. Astrocytes isolated from SAMP8 brain and those differentiated from SAMP8 neural stem cells show senescence hallmarks (SA‐β‐gal, p16INK4a, Lamin B1 loss), alongside a significant reduction in synaptogenic function. While astrocyte‐conditioned medium (ACM) from control mice promotes excitatory synaptogenesis through thrombospondin‐1/α2δ‐1 neuronal receptor signaling, ACM from senescent SAMP8 astrocytes lacks this capacity. Supplementing senescent ACM with thrombospondin‐1 protein or overexpressing thrombospondin‐1 gene in senescent astrocytes reinstates synaptogenesis. At the hippocampal level, thrombospondin‐1 and synaptic puncta are reduced in SAMP8 mice. Our findings reveal that senescent astrocytes exhibit reduced synaptogenic capacity due to thrombospondin‐1 loss, highlighting their contribution to synaptic dysfunction during aging. Preventing senescence in hippocampal astrocytes may thus restore astrocyte‐mediated synaptogenesis in the aged brain.

Senescent hippocampal astrocytes lose TSP secretion, impairing excitatory synaptogenesis via the α2δ‐1 pathway. Restoring TSP‐1 rescues synaptic formation, revealing the contribution of astrocyte senescence to age‐related hippocampal synaptic decline.

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