Affiliations: [a] Department of Neurology, Innovation Center for Neurological Disorders, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China | [b] Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China | [c] Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, P.R. China | [d] Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China | [e] Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, P.R. China | [f] National Clinical Research Center for Geriatric Disorders, Beijing, P.R. China | [g] Cerebrovascular Disease Research Institute, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China
Correspondence:
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Correspondence to: Jianping Jia, Department of Neurology, Innovation Center for Neurological Disorders, Xuan Wu Hospital, Capital Medical University, Beijing 100053, P.R. China. Tel.: +86 10 83198730; Fax: +86 1083171070; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Alzheimer’s disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-β peptides (Aβ) 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-β peptide (Aβ) were observed and evaluated in this PS1V97L plus hypoperfusion model. Compared with control mice, the model revealed significantly upregulated expression of Aβ (including Aβ oligomers), with decreased α-secretase activity and expression and increased β-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 Aβ transporters. Moreover, the model revealed decreased activity and expression of neprilysin, which is a peripheral Aβ degrading enzyme. These findings suggest that hypoperfusion may magnify the effect of AD on Aβ metabolism by aggravating its abnormal production, transport, and clearance.
