Article, Early Access,
Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions
Contributors
Park, Jae-Hyeon
0000-0001-5619-4818
[1]
[2]
Li, Zhiquan
0000-0003-3253-7606
[4]
Fang, Evandro
0000-0003-0355-7202
[5]
[6]
Affiliations
- [1] NIA, Computat Biol & Genom Core, LGG, Baltimore, MD USA [NORA names: United States; America, North; OECD];
- [2] NIA, Computat Biol & Genom Core, LGG, Baltimore, MD USA [NORA names: United States; America, North; OECD];
- [3] Tongji Univ, Frontier Sci Ctr Stem Cell Res, Sch Life Sci & Technol, Inst Regenerat Med,State Key Lab Cardiol & Med Inn, Shanghai 200092, Peoples R China [NORA names: China; Asia, East];
- [4] Univ Copenhagen, Danish Ctr Hlth Aging, ICMM, Copenhagen, Denmark [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
- [5] Norwegian Ctr Hlth Ageing NO Age, Oslo, Norway [NORA names: Norway; Europe, Non-EU; Nordic; OECD];
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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 (A beta) 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.
