EXERCISE reduced cognitive impairment and cerebral lipid accumulation in a mouse model of Alzheimer’s disease (AD), with researchers identifying microglial TMEM9 suppression as a potential mechanism underlying these effects. The findings suggest that exercise may support brain health by enhancing lipophagy, the process through which cells break down lipid droplets, and preserving mitochondrial function.
Researchers investigated the effects of a three month exercise intervention in 5×FAD transgenic mice, a model used to study AD. Cognitive and emotional behaviours were assessed alongside brain lipid accumulation and pathological changes. Laboratory experiments using microglial cells were also conducted to investigate the mechanisms involved.
Exercise reduced cerebral lipid droplet deposition by enhancing lipophagy, which was associated with preserved mitochondrial integrity and attenuated cognitive decline. These findings suggest that lipid metabolism and cellular waste clearance may be important components of the relationship between physical activity and neurodegenerative disease.
The study focused on microglia, immune cells in the central nervous system that contribute to the clearance of amyloid beta (Aβ). Researchers found that exercise suppressed expression of TMEM9, a protein implicated in impaired lipid droplet degradation.
Mechanistic investigations indicated that reduced TMEM9 expression facilitated the movement of liver kinase B1 (LKB1) to lysosomes, activating AMP activated protein kinase (AMPK) signalling. This pathway was associated with enhanced lipophagy and improved cellular protection.
In laboratory experiments, TMEM9 overexpression worsened impaired lipophagy and mitochondrial dysfunction, whereas TMEM9 knockdown enhanced lipid clearance and cytoprotection. Researchers also found that Aβ clearance was negatively regulated by TMEM9.
Interestingly, lipid droplets induced by oleic acid helped preserve mitochondrial membrane potential and increase adenosine triphosphate (ATP) production in microglial cells exposed to glucose deprivation and oligomeric Aβ. These findings highlight the complex role of lipid droplets in cellular energy maintenance, rather than suggesting that their accumulation is uniformly harmful.
The researchers also assessed plasma TMEM9 and ATP6AP1 levels in people with AD. Plasma TMEM9 correlated strongly with progression of phosphorylated tau 217 (p-tau217), while diagnostic analyses identified potential value in both TMEM9 and the TMEM9/ATP6AP1 ratio.
The area under the receiver operating characteristic curve (AUC) was 0.791 for TMEM9 and 0.853 for the TMEM9/ATP6AP1 ratio, indicating potential diagnostic discrimination that requires further validation.
Although these findings identify TMEM9 as a potential therapeutic target, the exercise intervention was conducted in mice, and the clinical biomarker findings do not establish that exercise produces the same effects in humans. Further research will be needed to determine whether targeting TMEM9 or enhancing lipophagy could translate into effective strategies for preventing or treating AD.
Reference
Zhang L et al. Exercise promotes lipophagy and mitigates cognitive impairment in Alzheimer’s disease through downregulating microglial TMEM9. Transl Neurodegener. 2026;15(1):56.
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