Acetylation is a common posttranslational modification in proteins that plays a vital role in health and diseases. Though acetylation affects ~10% of modified peptides in brain of Alzheimer’s disease; Aβ and tau containing aggregates have unusually high amounts. While, the accumulation of extracellular plaques of Aβ peptides is the major hallmark of Alzheimer’s disease, studies correlating different aggregate structures and its toxicity are lacking. Although, role of acetylation in several diseases including neurodegeneration have been explored for many proteins such as tau and histone; systematic studies on acetylation of lysine residues (K16, K28) for Aβ peptides on its aggregates structure and associated toxicity have not been reported.  Herein, we report effect of acetylation at K16 and K28 on Aβ42 peptides aggregation and toxicity. We explored the proteins physicochemical properties including aggregates structure by several techniques such as spectroscopy, fluorescence, and scanning electron microscopy. In addition, we tested these aggregates on SH-SY5Y cell lines (neuroblastoma) for their effect on cell viability, free radical generation, and cytotoxicity.  Our results show that acetylation at K16 disrupts amyloid formation and leads to amorphous aggregated structure that is flexible, shows increased hydrophobicity, and is highly toxic. Acetylation at K28 did not disrupt its amyloid forming ability. However, double acetylated peptides (acetylated at K16 and K28) show structure which are less flexible compared to K16Ac peptide but still forms amorphous aggregated structures and show high toxicity. And mixture of single or double acetylated peptides with WT Aβ42 showed higher toxicity compared to WT Aβ42 peptides alone with increased free radical formation. In summary, our results show that acetylation of Aβ42 peptides can impact its aggregation properties, kinetics, as well as cytotoxicity.<br/>

Acetylation at lysine residues modulates Aβ42 aggregates structure and cytotoxicity

2019 Spring National Meeting

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