The Effect of Chronic Cerebral Hypoperfusion on Amyloid-β Metabolism in a Transgenic Mouse Model of Alzheimer's Disease (PS1V97L).

Alzheimer's disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-beta peptides (A beta) in a living patient with AD. Thus, we developed an animal model of this condition, using transgenic mice (PS1V97L) and right common carotid artery ligation to create chronic cerebral hypoperfusion. The metabolic processes associated with amyloid-beta peptide (A beta) were observed and evaluated in this PS1V97L plus hypoperfusion model. Compared with control mice, the model revealed significantly upregulated expression of A beta (including A beta oligomers), with decreased alpha-secretase activity and expression and increased beta-secretase activity and expression. Furthermore, the model revealed increased mRNA and protein expression of the receptor for advanced glycation end products (RAGE) and decreased mRNA and protein expression of low-density lipoprotein receptor-related protein 1 (LRP-1); both these are A beta transporters. Moreover, the model revealed decreased activity and expression of neprilysin, which is a peripheral A beta degrading enzyme. These findings suggest that hypoperfusion may magnify the effect of AD on A beta metabolism by aggravating its abnormal production, transport, and clearance.