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

Neurobiol Dis. 2012 Jun;46(3):701-9. doi: 10.1016/j.nbd.2012.03.013. Epub 2012 Mar 9.


Alzheimer's disease (AD) is characterized by progressive memory loss due to extracellular senile plaques and intracellular neurofibrillary tangles. The toxic β-amyloid (Aβ) aggregates that form in AD can induce the overproduction of reactive oxygen species (ROS), nitric oxide (NO), and proinflammatory cytokines. These Aβ aggregates likely play a pivotal role in the onset and progression of AD. Reducing Aβ generation, inhibiting Aβ toxicity, and improving Aβ 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 Aβ cytotoxicity, increased the microglial phagocytosis of Aβ, decreased the Aβ-induced generation of ROS and NO, and attenuated the disequilibrium of calcium homeostasis in vitro. Remarkably, XD4 also attenuated memory deficits in β-amyloid precursor protein/presenilin 1 (APPswe/PS1dE9) transgenic mice, and reduced amyloid plaque burden and Aβ40/42 levels. The results of the present study indicate that this peptide, which specifically targets Aβ, may be a promising new therapy for patients exhibiting cognitive impairment and increased Aβ burden.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / psychology*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Blotting, Western
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cloning, Molecular
  • Coloring Agents
  • DNA / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Maze Learning / drug effects
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Memory Disorders / genetics
  • Mice
  • Mice, Transgenic
  • Microglia / drug effects*
  • Nitric Oxide / metabolism
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / toxicity*
  • Peptide Library
  • Peptides / pharmacology*
  • Phagocytosis / drug effects*
  • Reactive Oxygen Species / metabolism
  • Tetrazolium Salts
  • Thiazoles


  • Amyloid beta-Peptides
  • Coloring Agents
  • Peptide Fragments
  • Peptide Library
  • Peptides
  • Reactive Oxygen Species
  • Tetrazolium Salts
  • Thiazoles
  • XD4 peptide
  • amyloid beta-protein (1-42)
  • Nitric Oxide
  • DNA
  • thiazolyl blue
  • Calcium