Title

Blocking the apolipoprotein E/Amyloid-Beta interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice

Document Type

Journal Article

Publisher

IOS Press

Editor(s)

Dr. George Perry (Editor-in-Chief), Mark A Smith (Editor-in-Chief)

Faculty

Faculty of Computing, Health and Science

School

School of Exercise and Health Sciences

RAS ID

12322

Comments

This article was originally published as: Yang, J., Ji, Y., Mehta, P., Bates, K. A., Sun, Y., & Wisniewski, T. (2011). Blocking the apolipoprotein E/Amyloid-Beta interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice. Journal of Alzheimer's Disease, 24(2), 269-285. Original article available here

Abstract

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 Aβ12-28P, 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) Aβ PP mutations. These mice develop abundant CAA beginning at the age of 6 months. Behavioral results show that Aβ12-28P 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 Aβ12-28P 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.