Insulin-degrading enzyme deficiency accelerates cerebrovascular amyloidosis in an animal model

Abstract

Cerebrovascular amyloidosis (CA) may result in intraparenchymal bleeding and cognitive impairment. It was previously shown that transforming growth factor-β1 (TGF-β1) expression under an astrocyte promoter resulted in congophilic vascular deposits and vascular pathology. A reduction in insulin-degrading enzyme (IDE) activity was previously suggested to play a role in the accumulation of congophilic vascular deposits in the microvasculature of Alzheimer's disease (AD) cases. Here, we aim to investigate the link between TGF-β1 and IDE activity in the development of CA. We found that TGF-β1 can reduce IDE expression in a mouse brain endothelial cell line (ECs). Furthermore, we discovered that IDE activity in the brains of TGF-β1 transgenic (Tg) mice was significantly reduced compared with that of the control mice in an age-dependent manner. In addition, TGF-β1/IDE(-/-) mice showed significantly greater levels of cerebrovascular pathology compared with TGF-β1 mice. We have previously shown that 16-month-old TGF-β1 mice have a significant reduction in synaptophysin protein levels, which may lead to cognitive impairment. Here we discovered a significant reduction in synaptophysin protein already at the age of seven in the hippocampus of TGF-β1/IDE(-/-) mice compared with TGF-β1 mice. Further investigation of TGF-β1-mediated IDE activity in ECs may provide useful therapeutic intervention targets for cerebrovascular diseases such as CA.