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Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I
Meiling Wang1,2, Yumin Chang1,2, Aojie He1,2
1School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China.
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.
Insights
Secreted Phosphoprotein 1 (Spp1) in microglia is vital for memory in aging brains. Its deficiency impairs memory by affecting microglial function and energy production, highlighting Spp1
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.
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