title: Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease.
abstract: The amyloid-beta (Abeta) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of Abeta peptide constitutes a critical event in the early disease pathogenesis. The direct binding between Abeta and apolipoprotein E (apoE) is an important factor implicated in both Abeta clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/Abeta interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed Abeta12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length Abeta. Abeta12-28P binds with high affinity to apoE, preventing its binding to Abeta, but has no direct effect on Abeta aggregation. Abeta12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of Abeta plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of Abeta in two AD transgenic mice models. The treatment did not affect the levels of soluble Abeta fraction or Abeta oligomers, indicating that inhibition of the apoE/Abeta interaction in vivo has a net effect of increasing Abeta clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with Abeta12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.
authors.affiliation: Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. sadowm01@med.nyu.edu
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sadowski
authors.forename: Joanna
authors.initials: J
authors.lastname: Pankiewicz
authors.forename: Henrieta
authors.initials: H
authors.lastname: Scholtzova
authors.forename: Pankaj D
authors.initials: PD
authors.lastname: Mehta
authors.forename: Frances
authors.initials: F
authors.lastname: Prelli
authors.forename: David
authors.initials: D
authors.lastname: Quartermain
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001667:Binding, Competitive / Q000502:physiology; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C092395:amyloid beta-protein (12-28)