The Effect of Chronic Cerebral Hypoperfusion on Blood-Brain Barrier Permeability in a Transgenic Alzheimer’s Disease Mouse Model (PS1V97L)¹

Article type: Research Article

Authors: Yang, Heyun^{a; g} | Wang, Wei^{a; b; c; d; e; f} | Jia, Longfei^{a; b; c; d; e; f} | Qin, Wei^{a; b; c; d; e; f} | Hou, Tingting^a | Wu, Qiaoqi^{a; b; c; d; e; f} | Li, Haitao^a | Tian, Yuanruhua^a | Jia, Jianping^{a; b; c; d; e; f; *}

Affiliations: [a] Innovation Center for Neurological Disorders, Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China | [b] Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China | [c] Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, China | [d] Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China | [e] Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China | [f] National Clinical Research Center for Geriatric Disorders, Beijing, China | [g] Department of Neurology, The First Hospital of Kunming, Kunming, Yunnan, China

Correspondence: [*] Correspondence to: Jian-Ping Jia, Innovation Center for Neurological Disorders, Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing 100053, P.R. China. Tel.: +86 10 83198730; Fax: +86 1083171070; E-mail: [email protected].

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-239007, available at http://doi.org/10.3233/JAD-239007.

Abstract: The blood-brain barrier (BBB) can restrict the therapeutic effects of Alzheimer’s disease (AD) medications. While a large number of AD drug treatment trials targeting BBB dynamics have emerged, most have failed due to insufficient permeability. Furthermore, a subset of AD cases, which also feature chronic hypoperfusion are complicated by BBB deficits. We used a mouse model of AD with chronic hypoperfusion—transgenic mice (PS1V97L) with right common carotid artery ligation. In this model, we assessed how chronic cerebral hypoperfusion changed the pathophysiological processes that increase BBB permeability. Compared with control mice, AD mice with chronic hypoperfusion revealed significantly upregulated expression of the receptor for advanced glycation end products (RAGE) on the BBB. Upregulated RAGE caused increased accumulation of amyloid-β (Aβ) in the brain in these mice. Upregulation of RAGE (or binding to Aβ) can promote activation of the NF-κB pathway and enhance oxidative stress and increase the release of pro-inflammatory factors. These factors promoted the reduction of tight junction proteins between the endothelial cells in the BBB and increased its permeability. These findings suggest that the transporter RAGE dysregulation on the BBB initiates a series of pathophysiological processes which lead to increased BBB permeability. Taken together, we have shown that chronic hypoperfusion can serve to enhance and aggravate the BBB impairment in AD.

Keywords: Alzheimer’s disease, blood-brain barrier, chronic cerebral hypoperfusion, NF-κB pathway, permeability, transgenic mice

DOI: 10.3233/JAD-191045

Journal: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 261-275, 2020