A synthetic peptide blocking the apolipoprotein E/beta-amyloid binding mitigates beta-amyloid toxicity and fibril formation in vitro and reduces beta-amyloid plaques in transgenic mice.
Alzheimer's disease (AD) is associated with accumulation of beta-amyloid (Abeta). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Abeta, promoting its conformational transformation from soluble Abeta into toxic aggregates. We determined if blocking the apoE/Abeta interaction reduces Abeta load in transgenic (Tg) AD mice. The binding site of apoE on Abeta corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Abeta12-28P). This changed the peptide's properties, making it non-fibrillogenic and non-toxic. Abeta12-28P competitively blocks binding of full-length Abeta to apoE (IC50 = 36.7 nmol). Furthermore, Abeta12-28P reduces Abeta fibrillogenesis in the presence of apoE, and Abeta/apoE toxicity in cell culture. Abeta12-28P is blood-brain barrier-permeable and in AD Tg mice inhibits Abeta deposition. Tg mice treated with Abeta12-28P for 1 month had a 63.3% reduction in Abeta load in the cortex (P = 0.0043) and a 59.5% (P = 0.0087) reduction in the hippocampus comparing to age-matched control Tg mice. Antibodies against Abeta were not detected in sera of treated mice; therefore the observed therapeutic effect of Abeta12-28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Abeta and its pathological chaperones may be beneficial for treatment of beta-amyloid deposition in AD.
Sadowski
Marcin
M
Department of Neurology, New York University School of Medicine, New York, New York, USA.
Pankiewicz
Joanna
J
Scholtzova
Henrieta
H
Ripellino
James A
JA
Li
Yongsheng
Y
Schmidt
Stephen D
SD
Mathews
Paul M
PM
Fryer
John D
JD
Holtzman
David M
DM
Sigurdsson
Einar M
EM
Wisniewski
Thomas
T
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003164:Competitive Bidding; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D053764:Presenilin-1; D011485:Protein Binding / Q000187:drug effects; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1