Abstract
Alzheimer's disease (AD) presents many difficulties and has few available therapies. Because of their many advantages, polyphenolic metabolites of flavan-3-ol have gained attention as possible candidates for AD treatment. This work investigates the impact of these compounds on proteasome function in neuronal cells expressing genes related to AD. It finds that these compounds have inhibitory effects on proteasomes, especially in cells that have mutations in genes related to AD. Amyloid plaques, neurofibrillary tangles, oxidative stress, compromised autophagy, and proteasome systems, which affect protein clearance, are all components of AD pathology. Rich in anti-inflammatory and antioxidant qualities, polyphenols change into bioactive metabolites such as phenyl-γ-valerolactones. These metabolites alter Aβ oligomers and mitigate Aβ toxicity, potentially providing a therapeutic intervention for AD. The presented findings underscore the potential of various compounds, including C1, C2, C3, PGPH, and BrAAP, as modulators of proteasome function. The differential inhibitory effects observed on both constitutive (ChT-L) and immunoproteasome (T-L) activities signify the nuanced impact of these compounds. Notably, the selectivity of certain compounds towards either proteasome subtype suggests the possibility of targeted therapeutic strategies, particularly in the context of diseases associated with proteasome dysfunction, such as neurodegenerative disorders like Alzheimer's Disease. This study looks at how flavan-3-ol metabolites affect proteasome function and how they might be used as AD treatment agents. Understanding their effects on proteasomes opens avenues for novel AD treatments at a molecular level.