title: 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.
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Veronica
authors.initials: V
authors.lastname: Lifshitz
authors.forename: Tali
authors.initials: T
authors.lastname: Benromano
authors.forename: Ronen
authors.initials: R
authors.lastname: Weiss
authors.forename: Shani
authors.initials: S
authors.lastname: Blanga-Kanfi
authors.forename: Dan
authors.initials: D
authors.lastname: Frenkel
mesh_terms: D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002561:Cerebrovascular Disorders / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism; D007339:Insulysin / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016708:Synaptophysin / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016708:Synaptophysin; D053773:Transforming Growth Factor beta1; D007339:Insulysin