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Background: Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long-term treatment of AD and mechanisms of action are unknown., Methods: We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches., Results: Long-term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aβ) and tau pathologies and enhanced long-term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA-induced therapeutic effects on AD., Conclusions: Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA., Highlights: Long-term urolithin A (UA) treatment improved learning, memory, and olfactory function in Alzheimer's disease (AD) mice. UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein. UA modulates immune responses and AD-specific pathophysiological pathways., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

BACKGROUND: Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long‐term treatment of AD and mechanisms of action are unknown. METHODS: We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches. RESULTS: Long‐term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aβ) and tau pathologies and enhanced long‐term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA‐induced therapeutic effects on AD. CONCLUSIONS: Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA. Highlights: Long‐term urolithin A (UA) treatment improved learning, memory, and olfactory function in Alzheimer's disease (AD) mice.UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein.UA modulates immune responses and AD‐specific pathophysiological pathways. [ABSTRACT FROM AUTHOR]