These findings establish exercise-induced TMEM9 inhibition as a novel therapeutic strategy targeting lipidostasis to combat AD progression.
Key Findings
Results
Three months of exercise in 5×FAD mice reduced cerebral lipid droplet deposition by enhancing lipophagy, preserved mitochondrial integrity, and attenuated cognitive decline.
5×FAD transgenic mice underwent a three-month exercise intervention.
Cognition and emotional behavior were assessed with the Morris water maze, novel object recognition, and open field test.
LD deposition was evaluated by oil red O and BODIPY staining; pathology was examined by immunofluorescence, western blotting, and transmission electron microscopy.
Results
Exercise suppressed microglial TMEM9 expression, which restored lipid droplet degradation.
Proteomic sequencing was used to identify proteins affected by exercise, and TMEM9 emerged as the exercise-regulated protein.
Intracerebroventricular AAV injection was used to overexpress or knock down microglial TMEM9 in vivo to test its role in exercise effects on behavior and pathology.
Results
Tmem9 downregulation facilitated lysosomal translocation of LKB1 and activated AMPK signaling.
This was proposed as the mechanism by which reduced TMEM9 restores lipophagy.
The interaction between TMEM9 and ATP6AP1 was examined by co-immunoprecipitation.
Results
In BV2 microglia, oleic acid-induced lipid droplets preserved mitochondrial membrane potential and increased ATP production under glucose deprivation and oligomeric Aβ exposure.
BV2 cells were incubated with oligomeric amyloid-β, with or without oleic acid to induce LDs.
Chloroquine and rapamycin, which regulate autophagy-lysosomal function, were used to examine the effects of LDs on mitochondrial integrity under glucose deprivation.
Results
Tmem9 overexpression worsened lipophagy impairment and mitochondrial dysfunction, whereas Tmem9 knockdown enhanced lipophagy and cytoprotection.
Lentiviral or plasmid transfection was used to manipulate TMEM9 in vitro.
These experiments were used to establish TMEM9's key role in regulating lipophagy.
Results
Aβ clearance was negatively regulated by TMEM9.
This finding links TMEM9 levels to amyloid handling in addition to lipid droplet degradation.
Results
AD patients showed characteristic Aβ deposition and glucose hypometabolism, and plasma TMEM9 levels strongly correlated with p-tau217 progression.
Plasma TMEM9 and ATP6AP1 levels in AD patients were measured by ELISA.
The abstract does not give the correlation coefficient or patient numbers.
Results
Plasma TMEM9 and the TMEM9/ATP6AP1 ratio showed potential as AD diagnostic biomarkers, with the ratio performing better.
ROC analysis gave AUC = 0.791 for plasma TMEM9.
AUC = 0.853 for the TMEM9/ATP6AP1 ratio.
What This Means
This study looked at how exercise might protect the brain in Alzheimer's disease. In a mouse model of the disease, three months of exercise reduced the buildup of fat droplets in the brain, helped brain cells' recycling systems break those droplets down, protected the energy-producing mitochondria, and lessened memory and thinking problems. The effect appeared to work through a protein called TMEM9 in microglia, the brain's immune cells. Exercise lowered TMEM9, and this switched on a cellular energy-sensing pathway (LKB1–AMPK) that helps clear fat droplets.
In cell experiments, raising TMEM9 made recycling and mitochondrial function worse, while lowering it helped cells cope with stress and clear amyloid-β. Fat droplets themselves seemed to help microglia keep up energy production when sugar was scarce and amyloid-β was present, suggesting the balance of fat storage and breakdown matters.
In people with Alzheimer's disease, blood levels of TMEM9 tracked closely with p-tau217, a marker of disease progression. TMEM9, and especially its ratio to a partner protein called ATP6AP1, showed promise as a blood-based diagnostic marker. This research suggests TMEM9 could be a target for future therapies and a possible biomarker, but the findings come mainly from mice and cell models and would need confirmation in larger human studies.
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Zhang L, Li S, Ma X, Cheng S, Ye Z, Liu S, et al.. (2026). Exercise promotes lipophagy and mitigates cognitive impairment in Alzheimer's disease through downregulating microglial TMEM9.. Translational neurodegeneration. https://doi.org/10.1186/s40035-026-00583-z