Urolithin A Improves Alzheimer’s Disease Cognition and Restores Mitophagy and Lysosomal Functions

ABSTRACT Background Compromised autophagy, including impaired mitophagy and lysosomal function, is thought to play a pivotal role in Alzheimer’s disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of early and/or long-term treatment, as well as more detailed mechanisms of action, are not known. Methods We addressed these questions in three mouse models of AD, and behavioral, electrophysiological and biochemistry assays were performed. Results Long-term UA treatment significantly improved learning, memory and olfactory function in different AD transgenic mice. UA also reduced Aβ and Tau pathologies, and improved long-term potentiation. We found that UA activated autophagy/mitophagy via increasing lysosomal functions. At the cellular level, UA improved lysosomal function and normalized lysosomal cathepsins, especially targeting cathepsin Z, to restore lysosomal function in AD, indicating the important role of cathepsins in UA-induced therapeutic effects of AD. Conclusions Collectively, our study highlights the importance of lysosomal dysfunction in AD etiology, and points to the high translational potential of UA.