Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ1-42 and mutant Tau.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary Tau tangles, ultimately leading to brain atrophy and death. To elucidate the relationship between the aberrant folding and aggregation of Aβ and mutant Tau and neuronal function, we monitored neuronal activity in C. elegans AD models across age. For that, we used a neuronal GCaMP reporter to monitor fluctuations in Ca2+ and developed microfluidic devices to immobilize nematodes to non-invasively assess neuronal activity. Our findings revealed that expression of both Aβ and Tau lead to significant reductions in neuronal activity and function in young adult animals, preceding the accumulation of amyloid aggregates. Notably, Aβ expression and aggregation in muscle tissue produced detrimental effects on neuronal activity comparable to those seen after expression in neurons, suggesting that proteotoxic stress in muscle can influence neuronal function. This may occur through propagation of Aβ from muscle to neurons or through retrograde signaling pathways. Further, our new sub-stoichiometrically labeled Tau strains highlight the significant impact TauP301L,V337M has on neuronal activity throughout aging. These results enhance our understanding of the early functional effects of amyloid aggregation in Alzheimer's disease.