Screening And Functional Studies On Peptide Drugs For Alzheimer's Disease Treatment

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disease, characterized by memory decline and the formation of senile plaques in patient brains. Amyloidβ-peptide (Aβ) aggregates are implicated as the major causative agent in AD. Aβis derived from proteolytic processing of the amyloid precursor protein (APP) by means of BACE1 (β-secretase) andγ-secretase. Therefore, inhibition ofβ-,γ-secretase proteolytic activity also can inhibit the production of Aβ. However, recent evidence has shown that BACE may be involved in processing other non-APP substrates and simple inhibition ofβ-,γ-secretase may cause many side effects. Novel inhibitors intervening BACE proteolytic processing, through pre-binding on theβ-cleavage site of APP to blockβ-cleavage site of APP from the access of secretases, could reduce Aβproduction and avoid potential side effects of secretase inhibitors due to the non-specific inhibition of normal processing of essential proteins by secretasesWe present here a unique approach to inhibit Aβproduction by means of peptides specific binding to theβ-secretase cleavage site of APP. To obtain the peptides that may bind to substrate peptide corresponding to theβ-cleavage site of APP and AβN terminal, phage display technique was applied.Consensus sequences were obtained by positive clones DNA sequencing and amino acid sequence alignment. Selective peptides with therapeutic potential had high affinity and specificity to bindβ-sites and Aβpeptides.Some peptides could promote Aβ42 aggregation and the other peptides inhibit Aβ42 aggregation. Nevertheless, MTT results indicated that almost all of peptides could attenuate Aβ42-induced cytotoxicity.Further investigation showed that peptides LY3, S1, S6 and G5 could inhibit the processing of APP as well as the production of Aβin the 7PA2 cells. Animal experiments showed that S1 could improve spatial memory and reduce plaque burden in APP/PS1 mice.These small molecule peptides which have the ability to suppress Aβproduction, aggregation and cytotoxicity with less side effects, easy to penetrate blood-brain barrier, have potential practical value for AD treatment.