Effect of AmyTrap, an amyloid-β binding drug, on Aβ induced mitochondrial dysfunction and tau phosphorylation in cultured neuroblastoma cells.

Alzheimer's Disease (AD) is the most common cause of dementia, affecting 25 million people worldwide. Accumulation of Amyloid-β (Aβ) in the mitochondria has been shown to adversely affect key enzymes including pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), oxoglutarate dehydrogenase (OGDH). Accumulation of Aβ is also believed to increase Tau expression and pathology. Tau, in its toxic state, results in synaptic damage causing memory and cognitive dysfunction. We are developing a drug to treat AD namely AmyTrap. The active pharmacological ingredient is a retro inverso, Aβ-binding peptide which sequesters Aβ. We wanted to examine the effect of AmyTrap peptide on Aβ-induced mitochondrial dysfunction and Tau phosphorylation. Therefore, we treated SH-SY5Y neuroblastoma cells with wild-type Aβ, a mutant AβY10A, AmyTrap peptide (RI-peptide), or Aβ and RI-peptide for 72 h. The mutant AβY10A is known to impact the self-aggregating property of Aβ as this Tyr10 is essential for self-aggregation. As expected, AβY10A reversed PDH, OGDH and SDH dysfunction to near normal levels. Further, AβY10A successfully reversed Tau phosphorylation, suggesting that Tyr10 is also associated with Aβ-induced cytotoxicity. RI-peptide was able to significantly reverse SDH dysfunction with limited effect on PDH and Tau phosphorylation. The findings are suggestive that the Tyr10 on Aβ plays a critical role in the self-aggregation. Further studies are warranted to expand these findings.