I32E and V36K double mutation in ß2-sheet abrogates amyloid ß peptide toxicity.

ABSTRACT

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, wherein, the accumulation of amyloid ß(Aß) peptide as cytotoxic oligomers leads to neuropathologic changes. Transgenic mice with brain Aß plaques immunizedwith aggregated Aß have reduced amyloid burden and improved cognitive functions. However, such active immunization inhumans led to a small but significant occurrence of meningoencephalitis in 6% AD volunteers due to Aß induced toxicity. Inan attempt to develop safer alternative vaccines, the design of a highly soluble peptide homologous to Aß (Aß-EK), that hasa reduced amyloidogenic potential while maintaining the major immunogenic epitopes of Aß is reported. More importantly,this homologue has been shown to be non-toxic, as this peptide failed to exert any observable effect on erythrocytes. Theresults of the present study suggests that immunization with non-toxic Aß derivative may offer a safer therapeutic approachto AD, instead of using toxic Aß fibrils.