TY - JOUR
T1 - Insulin-degrading enzyme deficiency accelerates cerebrovascular amyloidosis in an animal model
AU - Lifshitz, Veronica
AU - Benromano, Tali
AU - Weiss, Ronen
AU - Blanga-Kanfi, Shani
AU - Frenkel, Dan
N1 - Funding Information:
This work was supported by grants from the Alzheimer’s association and the ISF legacy 1092/11 (to D.F.). There are no conflicts of interest. We wish to thank Prof. Dennis Selkoe for the IDE −/− mice and helpful advice and Prof. Tony Wyss-Coray for the TGF-β1 mice. We wish to thank Ronit Galron for her help with immunohistology.
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Cerebrovascular disease
KW - Endothelial cells
KW - Insulin-degrading enzyme
KW - TGF-β1
UR - http://www.scopus.com/inward/record.url?scp=84876821740&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2012.12.003
DO - 10.1016/j.bbi.2012.12.003
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AN - SCOPUS:84876821740
SN - 0889-1591
VL - 30
SP - 143
EP - 149
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -
