Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ and mutant Tau.

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 AD models across age. Our findings reveal 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 comparable detrimental effects on neuronal activity as its expression in neurons, suggesting that proteotoxic stress in muscle can influence neuronal function. This may occur through the propagation of Aβ from muscle to neurons or through retrograde signaling pathways. Further, our new sub-stoichiometrically labeled Tau strains highlight that Tau has a significant impact on neuronal activity throughout aging. These results enhance our understanding of the early functional effects of amyloid aggregation in Alzheimer's disease.