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 hypothesised that cerebral hypoperfusion promotes the accumulation of amyloid-β (Ab) 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 Ab peptide pools in a transgenic mouse model of AD (Tg-SwDI) at an age when fibrillar amyloid burden is minimal. Cerebrovascular integrity was characterised by quantifying the occurrence of microinfarcts and haemorrhages and compared to wild-type mice without Ab. A significant increase in soluble Ab peptides (Aβ40/42) was detected after 1 month of hypoperfusion in the parenchyma in parallel with elevated amyloid precursor protein (APP) and APP proteolytic products. Following 3 months, a significant increase in insoluble Aβ40/42 was determined in the parenchyma and vasculature. Microinfarct load was significantly increased in the Tg-SwDI as compared to wild-type mice and further exacerbated by hypoperfusion at one and three months. In addition, the number of Tg-SwDI hypoperfused mice with haemorrhages was increased compared to hypoperfused wild-type mice. Soluble parenchymal Aβ was associated with elevated NADPH Oxidase-2 (NOX2) which was exacerbated by one month hypoperfusion. We suggest that in response to hypoperfusion, increased Aβ production/deposition may contribute to degenerative processes by triggering oxidative stress promoting cerebrovascular disruption and the development of microinfarcts.
- Journal Article