AMPK Modulates Associative Learning via Neuronal Mitochondrial Fusion inC. elegans

Abstract

Loss of metabolic homeostasis is one of the hallmarks of the aging process that might contribute to pathogenesis by creating a permissive landscape over which neurodegenerative diseases can take hold. AMPK, a conserved energy sensor, extends lifespan and is protective in some neurodegenerative models. AMPK regulates mitochondrial homeostasis and morphology, however, whether mitochondrial regulation causally links AMPK to protection against loss of neuronal function with aging and diseases remains unclear. Here we use an associative learning protocol in C. elegans as a readout of neuronal function and show that AMPK activation enhances associative learning and prevents age-related loss of learning capacity. AMPK promotes neuronal mitochondrial fusion and driving mitochondrial fragmentation via fzo-1 deletion blocks AMPK's effects on associative learning. Restoring mitochondrial fusion capacity specifically in the neurons rescues learning capacity downstream of AMPK. Finally, AMPK activation rescues neuronal Aβ42 induced loss of associative learning. Overall, our results suggest that targeting neuronal metabolic flexibility may be a viable therapeutic option to restore neuronal function in the context of aging and neurodegenerative diseases.

Detecting Brain Structure-Specific Methylation Signatures and Rules for Alzheimer’s Disease

“…Moreover, TBC1D1 may be precisely regulated by effective microRNAs, thereby contributing to the development and aging of the central nervous system ( Sephton et al, 2012 ). An in vivo study based on the model organism Caenorhabditis elegans confirmed that TBC1D1 in HIPPO may be functionally correlated with aging-related diseases ( Escoubas-GüNey, 2018 ). Although this study did not cover AD, it nevertheless confirmed the tissue specificity of this gene.…”