Figure caption:
From organismal, bioinformatical, cellular and biochemical aspects, the effects and mechanisms of Urolithin A (UA) were investigated. We used different mouse models (including APP/PS1, 3xTgAD and 3xTgAD/Polβ+/-), and found that UA treatment improve behaviors, decreased inflammation and microglia hyperactivation. By using RNA-seq and NanoString, lysosomal pathways and gene were enrichment after UA treatment. RNA and protein levels of some lysosomal cathepsins are altered by UA treatment. We propose that UA inhibits CTSZ activity, to decrease Aβ and inflammation and induces mitophagy.
Urolithin A improves Alzheimer’s disease cognition and restores mitophagy and lysosomal functions
Alzheimer’s & Dementia, 2024
doi: https://doi.org/10.1002/alz.13847
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.