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

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. APP/PS1 mice were treated with daily gavage of Urolithin A (20mg/kg/day) or not (water) by gavage from 2m of age til 7m of age, then hippocampi were collected. Thereafter, some mice (washout groups) ceased gavage and were allowed to age one more month before hippocampi were collected. Samples were: controls (n=4), APPPS1_control (n=3), APPPS1_UA (n=4), washout controls (n=5), washout APPPS1 controls (n=3), and washout APPPS1_UA (n=5).