Potential anti-amyloid beta oligomerization effects of PD166793 in Alzheimer's disease

초록

Alzheimer' disease (AD) is the most common neurodegenerative disorder, driven by aggregation of amyloid-beta (A(3) oligomers and causing neuronal damage and cognitive decline. Despite advancements in AD drug development, many treatments remained expensive and often lacked with long-term efficacy. This highlighted the urgent need for small-molecule therapeutics that the strategy of specifically targeting A(3 oligomers with emerging drug repositioningcould be promising. In this study, we investigated the repositioned compound PD166793 for its effects on A(3 oligomers and AD pathology. A screening of bioactive molecules or compounds identified PD166793 as a potent inhibitor of A(342 aggregation, which significantly reduced A(342 oligomerization. Its direct interaction with A(342 was confirmed by surface plasmon resonance and computational docking system. The PD166793 recovered A(342-induced toxicity and improved the mitochondrial functions in SH-SY5Y cells. AD therapeutic potentials of PD166793 were assessed in 5xFAD (B6SJL) transgenic mice. In these mice, PD166793 significantly improved cognitive performance, reduced A(3 plaque deposition, and decreased neuroinflammation and apoptosis in the brain, including reduced microglial activations and caspase-3 expressions. These findings supported that PD166793 would be a potent inhibitor of A(342 oligomerization with neuroprotective effects in both cellular and animal models. Its ability to reduce A(3 plaque formation, alleviate neuroinflammation, and protect neurons from apoptosis accentuated its potential as a repositioned therapeutic agent for AD.

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