A Potentially Detrimental Pin1 in Cerebrovascular Pathology: Beyond its Traditionally Beneficial Regulation of Amyloid–β and Tau

Some novel neurological studies highlight the pathogenic associations of amyloid-β, tau and genetic polymorphisms with cognitive impairment, Alzheimer’s disease (AD), etc. [1-4]. To our knowledge, the pathogenic mechanisms of cognitive impairment and AD are very complicated. Amongst relevant risk factors, cerebrovascular infarction and microvessel ischemia play very crucial roles in the development of these neurological diseases [5-8]. Several recent studies tried to explore potential molecular mechanisms underlying cerebral vascular infarction and their relationships with neurological disorders. For example, Raghib et al. found that calcified cerebral emboli result in vascular occlusion and acute stroke in 3 patients, and a simple thrombolysis treatment was not very effective for them [9]. Diacinti et al. described 4 rare cases with cerebral venous thrombosis, which lacks typical vascular signs Received: October 24, 2019


Introduction
Some novel neurological studies highlight the pathogenic associations of amyloid-β, tau and genetic polymorphisms with cognitive impairment, Alzheimer's disease (AD), etc. [1][2][3][4]. To our knowledge, the pathogenic mechanisms of cognitive impairment and AD are very complicated. Amongst relevant risk factors, cerebrovascular infarction and microvessel ischemia play very crucial roles in the development of these neurological diseases [5][6][7][8]. Several recent studies tried to explore potential molecular mechanisms underlying cerebral vascular infarction and their relationships with neurological disorders. For example, Raghib et al.
found that calcified cerebral emboli result in vascular occlusion and acute stroke in 3 patients, and a simple thrombolysis treatment was not very effective for them [ As can be seen, the molecular mechanisms underlying cerebral thrombus and occlusion formation are very complicated, and one major explanation is reduced cerebral vasodilatation, which necessitates further identifying novel molecular basis of vasodilative reduction. In accordance with these ideas, we intend to suggest a potential role of the peptidyl-prolyl cis-trans isomerase Pin1 in these bioactive processes.

Patients Description
A few patients with cerebral infarction (and/or coronary heart disease) were randomly selected from the Affiliated Hospital of Hebei University of Engineering in 2018 and 2019. Each of them signed the informed consent and answered the questionnaire.

Blood Preparation, DNA Extraction, PCR Amplification and Gene Sequencing
All reagents for DNA sequencing were provide by the Sangon Biotech, Shanghai. 5 mL peripheral blood was collected, and blood cells were separated by centrifugation (3000 rpm, 10 min, stored at -80℃). DNA was extracted by Ezup Column Blood Genomic DNA Extraction Kit, and then PCR assays were performed. DNA sequences were measured by the 3730XL DNA Analyzer. The PCR primers for nine single nucleotide polymorphism (SNP) sites of Pin1 were shown in our previous studies [14].

Results and Discussions
The

A New Pin1-Based Hypothesis for Cerebrovascular Pathology and Ischemia-Related Neurological Disorders
Pin1 is the only known isomerase that regulates cis-trans structural transition and phosphorylation of many signaling proteins (pThr/pSer-Pro motifs) [18,19]. Previously, it is well known that amyloid-β deposition and tau aggregation are two major molecular pathologies in cerebral disorders especially AD, but Pin1 regulates processing of amyloid precursor protein and reduces amyloid-β and tau aggregates [19][20][21]. In this sense, Pin1 beneficially protects brain tissues from AD and relevant neurological disorders. However, on the basis of a novel cerebral vasodilatation signaling pathway, we herein underline a potentially detrimental link between Pin1 and cerebrovascular thrombosis-related neuropathies. Nitric oxide (NO) has an evident vessel-relaxing/vasodilatation bioactivity and is a key target of cardiovascular drugs [18,22] showed that Pin1 impairs NO activity in HAECs and diabetic mouse model [26].
Hypothetically, suppression of eNOS activity and NO production by Pin1 may attenuate the dynamic contraction-dilatation movement of cerebral blood vessels and thus result in precipitation/ deposition of plasma components onto cerebrovascular walls, thrombosis, atherosclerosis, and so on. These findings put forward a novel but detrimental Pin1-based etiological hypothesis for cerebral neuropathology, which is different from the previouslyknown beneficial roles of Pin1 in neurological disorders such as AD via suppressing amyloid-β and tau aggregation.

Future Orientations and Limitations
In summary, this work succinctly suggests that Pin1 may aggravate thrombotic neuropathies, and Pin1 genetic polymorphism may represent a new genetic and molecular basis for neurological pathologies resulting from cerebrovascular thrombosis.