A multifunctional peptide rescues memory deficits in Alzheimer's disease transgenic mice by inhibiting Aβ42-induced cytotoxicity and increasing microglial phagocytosis

Alzheimer's disease (AD) is characterized by progressive memory loss due to extracellular senile plaques and intracellular neurofibrillary tangles. The toxic beta-amyloid (A beta) aggregates that form in AD can induce the overproduction of reactive oxygen species (ROS), nitric oxide (NO), and proinflammatory cytokines. These A beta aggregates likely play a pivotal role in the onset and progression of AD. Reducing A beta generation, inhibiting A beta toxicity, and improving A beta clearance are promising therapeutic strategies for AD. The present paper is the first to reveal a heptapeptide (XD4) isolated from a Ph.D.-C7C library through phage display that significantly inhibited A beta cytotoxicity, increased the microglial phagocytosis of A beta, decreased the A beta-induced generation of ROS and NO, and attenuated the disequilibrium of calcium homeostasis in vitro. Remarkably, XD4 also attenuated memory deficits in beta-amyloid precursor protein/presenilin 1 (APPswe/PS1dE9) transgenic mice, and reduced amyloid plaque burden and A beta 40/42 levels. The results of the present study indicate that this peptide, which specifically targets A beta, may be a promising new therapy for patients exhibiting cognitive impairment and increased A beta burden. (C) 2012 Elsevier Inc. All rights reserved.