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Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating β/γ-Secretases

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Abstract

Chronic cerebral hypoperfusion (CCH) contributes to the Alzheimer’s-like pathogenesis, but the relationship between CCH and the occurrence of Alzheimer’s disease (AD) remains obscure. The aim is to elucidate the potential pathophysiological mechanism in the field of amyloid-beta (Aβ) pathology induced by CCH. A rat model of CCH has been developed with permanent bilateral occlusion of common carotid arteries (BCCAO). The cognitive function of rats was tested by the Morris water maze. The levels of Aβ (Aβ40 and Aβ42) and soluble amyloid precursor protein (sAPP: sAPPα and sAPPβ) were determined by enzyme linked immunosorbent assay. The expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), presenilin1 (PS1), nicastrin (NCT), anterior pharynx-defective 1alpha (Aph-1α) and presenilin enhancer 2 (Pen-2), sAPPα and sAPPβ were detected by Western blotting. Morris water maze test showed that CCH induced decline in learning and memory related to Aβ levels in the hippocampus. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of CCH rats were higher than the control ones (P < 0.05); the levels of sAPPβ, BACE and BACE1 increased more than the control ones (P < 0.05). CCH intervention (1-week or 4-week) markedly increased the expression of PS1, Aph-1α and Pen-2 in the hippocampus of rats, but had no effect on NCT. CCH contributed to cognitive impairment and altered the amyloidogenic and non-amyloidogenic pathway of APP processing by boosting the activity of β-secretase/γ-secretase and α-secretase respectively. The non-amyloidogenic pathway can’t overcome the damage role of the amyloidogenic pathway in the process of chronic cerebral hypoperfusion which promotes amyloid-beta pathogenesis.

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Acknowledgements

This work was supported by grants from by the Natural Science Foundation of Hubei Province (2015CFB260), and the Hubei Province Health and Family Planning Scientific Research Project (WJ2015MB219) and the Shiyan Natural Science Foundation (15K70) and Chongqing General Hospital to Dr Zhiyou Cai.

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  1. Zhiyou Cai and Zhou Liu equally contributed to this work.

Authors and Affiliations

  1. Department of Neurology, Chongqing General Hospital, Chongqing, No. 312 Zhongshan First Road, Yuzhong District, Chongqing, 400013, People’s Republic of China

    Zhiyou Cai

  2. Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

    Zhou Liu

  3. Department of Neurology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524023, Guangdong, People’s Republic of China

    Zhou Liu

  4. Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People’s Republic of China

    Ming Xiao

  5. Department of Pathology, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Chuanling Wang

  6. Department of Neurology, Renmin Hospital, Hubei University of Medicine, No. 39 Chaoyang Middle Road, Shiyan, 442000, Hubei, People’s Republic of China

    Fuming Tian

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  1. Zhiyou Cai
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  2. Zhou Liu
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  3. Ming Xiao
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Correspondence to Zhiyou Cai or Fuming Tian.

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Cai, Z., Liu, Z., Xiao, M. et al. Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating β/γ-Secretases. Neurochem Res 42, 3446–3455 (2017). https://doi.org/10.1007/s11064-017-2391-9

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