Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I...

Area of Science:

• Neuroscience
• Immunology
• Aging Research

Background:

• Age-related memory decline is a significant risk factor for neurodegenerative diseases.
• Microglia are essential for brain homeostasis and memory preservation via phagocytosis.
• The precise mechanisms of microglial protective functions in aging remain unclear.

Purpose of the Study:

• To investigate the role of Secreted Phosphoprotein 1 (Spp1) in microglia during brain aging.
• To elucidate the molecular mechanisms by which microglial Spp1 influences age-dependent memory deficits.

Main Methods:

• Identification of Spp1-positive microglia in aged mouse and human brains.
• Generation and analysis of microglia-specific Spp1 knockout (Spp1-cKO) mice.
• Assessment of memory function, microglial phagocytosis, and the AKT/mitochondrial pathway.

Main Results:

• Spp1 deficiency selectively caused memory deficits in aged mice, not young mice.
• Microglial phagocytic capacity and Spp1 levels showed a positive correlation.
• Spp1 deficiency impaired the AKT/mitochondrial complex I pathway, reducing oxidative phosphorylation.

Conclusions:

• Microglial Spp1 plays a critical, age-dependent role in maintaining memory function.
• Spp1 regulates microglial phagocytosis and energy metabolism via the AKT/mitochondrial pathway.
• This study reveals Spp1 as a novel therapeutic target for age-related memory decline.