Blocking the Apolipoprotein E/Amyloid-β Interaction Reduces Fibrillar Vascular Amyloid Deposition and Cerebral Microhemorrhages in TgSwDI Mice

The accumulation of amyloid-beta (A beta) peptides as toxic oligomers, amyloid plaques, and cerebral amyloid angiopathy (CAA) is critical in the pathogenesis of Alzheimer's disease (AD). The binding of A beta peptides to apolipoprotein E (ApoE) plays an important role in modulation of amyloid deposition and clearance. We have shown that blocking the A beta/ApoE interaction with A beta(12-28P), a nontoxic blood-brain-barrier permeable and non-fibrillogenic synthetic peptide, constitutes a novel therapeutic approach for AD by reducing A beta 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) A beta PP mutations. These mice develop abundant CAA beginning at the age of 6 months. Behavioral results show that A beta(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 A beta levels in the brain homogenate revealed a significant decrease in both the total amount of A beta and A beta oligomer levels in A beta(12-28P) treated TgSwDI mice. These findings suggest that blocking the A beta/ApoE interaction is a highly effective therapeutic approach for vascular amyloid deposition, in contrast to some other therapeutic approaches.