Deficiency of Microglial‐Derived Spp1 Exacerbates Age‐Related Memory Decline by Impairing Mitochondrial Complex I Function

TL;DR

This study shows that a protein called Spp1, produced by brain immune cells, helps prevent memory loss in aging by supporting energy production in these cells.

Contribution

The study reveals a new mechanism by which microglial Spp1 prevents age-related memory decline through the AKT/Complex I pathway.

Findings

Spp1 deficiency in microglia worsens memory decline in aged mice.

Spp1 supports microglial function by regulating the AKT/mitochondrial complex I pathway.

Overexpression of Spp1 in microglia can partially reverse age-related memory issues.

Abstract

Age‐related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)‐positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia‐specific Spp1 knockout (Spp1‐cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age‐dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia‐specific overexpression of Spp1 partially ameliorates the age‐related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age‐related memory decline.

Microglia‐derived Spp1 regulates OXPHOS via the AKT/Complex I pathway to mitigate age‐related memory decline. (Graphical Abstract was created using BioRender).

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