Pin1, endothelial nitric oxide synthase, and amyloid-β form a feedback signaling loop involved in the pathogenesis of Alzheimer's disease, hypertension, and cerebral amyloid angiopathy

Jing-Zhang Wang, Wang-Dong Zhu, Zhong-Xin Xu, Wen-Tao Du, Hong-Yan Zhang, Xue-Wen Sun, Xiao-Hua Wang
Medical Hypotheses 2014, 82 (2): 145-50
Although the molecular mechanism has not yet been clarified until now, it is very interesting that Alzheimer's disease (AD), hypertension (HTN), and cerebral amyloid angiopathy (CAA) often occur synchronously and possess many similar pathological characteristics. Herein, we hypothesize that a feedback signaling loop, consisted of Pin1, endothelial nitric oxide synthase (eNOS), and amyloid-β (Aβ), may contribute to the interesting pathological phenomenon. First, Pin1 inhibits the production of Aβ, and enhances the activity of eNOS. Second, Aβ and eNOS form a mutual inhibition system. Third, the well-balanced feedback signaling loop avoids the development of AD, HTN, and CAA by inhibiting the frequent pathological characteristics of these diseases, including Aβ deposition in cerebral microvessels and cerebral microbleeds. On one hand, Pin1 and eNOS not only inhibit Aβ production but also accelerate Aβ clearance, preventing Aβ deposition in cerebral microvessels. On the other hand, Pin1 and eNOS promote vasodilatation and prevent the elevation of blood pressure in brain, alleviating the pathology of cerebral microbleeds. However, once the precise balance is disturbed, it may result in Aβ deposition, microbleeds, and elevated blood pressure, possibly leading to the synchronous occurrence of AD, HTN, and CAA. The hypothesis updates the current understanding of the molecular linkage among AD, HTN, and CAA, and lays the ground for developing combined prevention, diagnosis, and treatment of these diseases more efficiently and more economically. Interestingly, biotechnical medicines enhancing the activity of Pin1 and/or eNOS may prevent the development of AD, HTN, and CAA, and targeting Aβ deposition may alleviate the clinical pathologies of these related diseases.

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