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Long-term Urolithin A treatment ameliorates disease pathology in Alzheimer's Disease mouse models [MET_DC]

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with learning, memory, and cognitive deficits. Neuroinflammation and lysosomal dysfunction are thought to play key roles in the progression of AD pathology. Diverse measures have been applied to treat AD, but currently, there is no effective treatment. Urolithin A (UA) is a gut microbial metabolite of ellagic acid shown to stimulate mitophagy and acts as a potent anti-inflammatory and anti-oxidant agent. However, long-term safety and the potential role of UA in altering pathology of AD is still largely unclear. In this study, we investigated the underlying mechanisms for the beneficial effects of UA in multiple mouse models of AD. We report that long-term UA treatment significantly improves learning and memory, olfactory function, and synaptic function of neurons in AD transgenic mice. We demonstrate that UA decreases soluble and insoluble Ab1-42, total Tau, and Tau phosphorylation. Furthermore, alterations in lysosomal cathepsins, particularly upregulation of cathepsin Z, was observed in the AD mice brains and normalized by UA treatment. Notably, UA treatment also ameliorates neuroinflammation, DNA damage, mitochondrial dysfunction, and restores lysosomal functions in AD mice brains. Collectively, these results provide new insights into the role of UA in regulating lysosomal dysfunction, cathepsins, and suggests that UA may have a potential therapeutic application for AD. To understand what metabolism-related gene expression changes are induced by Urolithin A, WT (C57BL6/J), 3xTgAD and 3xTgAD/PolB+/- mice were treated with water or Urolithin A (200mg/kg/day) by oral gavage for 5 months starting when the mice were 12m of age, thereafter hippocampi tissues was collected from each mouse and subjected to RNA isolation.

ORGANISM(S): Mus musculus

PROVIDER: GSE214416 | GEO | 2024/07/01

REPOSITORIES: GEO

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Long-term Urolithin A treatment ameliorates disease pathology in Alzheimer's Disease mouse models [MET_DC]

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