Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions

Yujun Hou*, Xixia Chu, Jae Hyeon Park, Qing Zhu, Mansoor Hussain, Zhiquan Li, Helena Borland Madsen, Beimeng Yang, Yong Wei, Yue Wang, Evandro F. Fang, Deborah L. Croteau, Vilhelm A. Bohr

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
JournalAlzheimer's and Dementia
Volume20
Issue number6
Pages (from-to)4212-4233
Number of pages22
ISSN1552-5260
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Keywords

  • Alzheimer's disease
  • autophagy
  • cathepsin Z
  • DNA repair
  • lysosome
  • mitophagy
  • neuroinflammation
  • urolithin A

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