Human apolipoprotein A-I binds amyloid-beta and prevents Abeta-induced neurotoxicity.
Aggregates of the amyloid-beta peptide (Abeta) play a central role in the pathogenesis of Alzheimer's disease (AD). Identification of proteins that physiologically bind Abeta and modulate its aggregation and neurotoxicity could lead to the development of novel disease-modifying approaches in AD. By screening a phage display peptide library for high affinity ligands of aggregated Abeta(1-42), we isolated a peptide homologous to a highly conserved amino acid sequence present in the N-terminus of apolipoprotein A-I (apoA-I). We show that purified human apoA-I and Abeta form non-covalent complexes and that interaction with apoA-I affects the morphology of amyloid aggregates formed by Abeta. Significantly, Abeta/apoA-I complexes were also detected in cerebrospinal fluid from AD patients. Interestingly, apoA-I and apoA-I-containing reconstituted high density lipoprotein particles protect hippocampal neuronal cultures from Abeta-induced oxidative stress and neurodegeneration. These results suggest that human apoA-I modulates Abeta aggregation and Abeta-induced neuronal damage and that the Abeta-binding domain in apoA-I may constitute a novel framework for the design of inhibitors of Abeta toxicity.
Paula-Lima
Andréa C
AC
Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brazil.
Tricerri
M Alejandra
MA
Brito-Moreira
Jordano
J
Bomfim
Theresa R
TR
Oliveira
Fabio F
FF
Magdesian
Margaret H
MH
Grinberg
Lea T
LT
Panizzutti
Rogerio
R
Ferreira
Sérgio T
ST
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
C505693:APOA1 protein, human; D016229:Amyloid beta-Peptides; D016632:Apolipoprotein A-I; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)