期刊
CLINICAL SCIENCE
卷 131, 期 16, 页码 2109-2123出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20170962
关键词
-
资金
- AXA Foundation [CT-0588]
- Alzheimer Society [152 (PG-157)]
- Alzheimer Research U.K. [ART-PG2010-3, ARUK-PG2013-22]
- University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the Cross Council Lifelong Health and Wellbeing Initiative [G0700704/84698]
Cerebral hypoperfusion is an early feature of Alzheimer's disease (AD) that influences the progression from mild cognitive impairment to dementia. Understanding the mechanism is of critical importance in the search for new effective therapies. We hypothesized that cerebral hypoperfusion promotes the accumulation of amyloid-beta (A beta) and degenerative changes in the brain and is a potential mechanism contributing to development of dementia. To address this, we studied the effects of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis on A beta peptide pools in a transgenic mouse model of AD (transgenic mice with Swedish, Dutch and Iowa mutations in human amyloid precursor protein (APP) (Tg-SwDI)). Cerebrovascular integrity was characterized by quantifying the occurrence of microinfarcts and haemorrhages and compared with wild-type mice without A beta. A significant increase in soluble A beta peptides (A beta 40/42) was detected after 1 month of hypoperfusion in the parenchyma in parallel with elevated APP and APP proteolytic products. Following 3 months, a significant increase in insoluble A beta 40/42 was determined in the parenchyma and vasculature. Microinfarct load was significantly increased in the Tg-SwDI as compared with wild-type mice and further exacerbated by hypoperfusion at 1 and 3 months. In addition, the number of Tg-SwDI hypoperfused mice with haemorrhages was increased compared with hypoperfused wild-type mice. Soluble parenchymal A beta was associated with elevated NADPH oxidase-2 (NOX2) which was exacerbated by 1-month hypoperfusion. We suggest that in response to hypoperfusion, increased A beta production/deposition may contribute to degenerative processes by triggering oxidative stress promoting cerebrovascular disruption and the development of microinfarcts.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据