The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS

Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.