Blocking the apolipoprotein E/amyloid-β interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice.
The accumulation of amyloid-β (Aβ) peptides as toxic oligomers, amyloid plaques, and cerebral amyloid angiopathy (CAA) is critical in the pathogenesis of Alzheimer's disease (AD). The binding of Aβ peptides to apolipoprotein E (ApoE) plays an important role in modulation of amyloid deposition and clearance. We have shown that blocking the Aβ/ApoE interaction with Aβ(12-28P), a nontoxic blood-brain-barrier permeable and non-fibrillogenic synthetic peptide, constitutes a novel therapeutic approach for AD by reducing Aβ parenchymal deposition. In the present study, we investigate this therapeutic effect on CAA in the transgenic (Tg) AD mice model (TgSwDI), which expresses Swedish (K670N/M671L), Dutch (E693Q)/Iowa (D694N) AβPP mutations. These mice develop abundant CAA beginning at the age of 6 months. Behavioral results show that Aβ(12-28P) treated TgSwDI AD mice performed the same as wild-type mice, whereas vehicle treated TgSwDI were impaired in spatial memory. Furthermore, this treatment resulted in a significant reduction of total amyloid burden, especially the fibrillar vascular amyloid burden, which importantly was accompanied by a reduction in microhemorrhages and neuroinflammation. Measurement of Aβ levels in the brain homogenate revealed a significant decrease in both the total amount of Aβ and Aβ oligomer levels in Aβ(12-28P) treated TgSwDI mice. These findings suggest that blocking the Aβ/ApoE interaction is a highly effective therapeutic approach for vascular amyloid deposition, in contrast to some other therapeutic approaches.
Department of Neurology, New York University School of Medicine, New York, NY 10016, USA.
Jing
J
Yang
Yong
Y
Ji
Pankaj
P
Mehta
Kristyn A
KA
Bates
Yanjie
Y
Sun
Thomas
T
Wisniewski
D000544:Alzheimer Disease / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors
D000682:Amyloid; 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)
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