Stefano George B, Esch Tobias, Ptacek Radek, Kream Richard M
Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.
Faculty of Health, School of Medicine, University Clinic for Integrative Health Care, Institute for Integrative Health Care and Health Promotion, Witten/Herdecke University, Witten, Germany.
Med Sci Monit. 2020 Sep 25;26:e927739. doi: 10.12659/MSM.927739.
Current critical thinking has displaced the elaborated beta amyloid theory as the underlying unitary mechanism of Alzheimer disease (AD) in favor of concerted, long-term disruption or dysregulation of broad-based physiological processes. We present a critical discussion in which a chronic state of systemic proinflammation sustained over the course of several decades and engendered by ongoing metabolic or autoimmune disease is predicted to promote severe disruptions of central neurological processes. Specifically, long-term functional rundown of microglial-mediated phagocytic activity in concert with aberrant expression and cellular deposition of beta amyloid and tau protein facilitates formation of senile plaques and neurofibrillary tangles. Within this functional context, we hypothesize that early initiation events in the pathophysiology of AD may operationally involve a convergence of dysregulated peripheral and central constitutive nitric oxide signaling pathways resulting from a chronic state of systemic proinflammation and leading to severely dysfunctional "hyperactivated" microglia.
当前的批判性思维已取代详尽的β淀粉样蛋白理论，成为阿尔茨海默病（AD）潜在的统一机制，转而支持广泛生理过程的协同、长期破坏或失调。我们进行了一场批判性讨论，预计由持续的代谢或自身免疫性疾病引发的、持续数十年的全身性促炎慢性状态会促进中枢神经过程的严重破坏。具体而言，小胶质细胞介导的吞噬活性的长期功能衰退，与β淀粉样蛋白和tau蛋白的异常表达及细胞沉积共同作用，促进了老年斑和神经原纤维缠结的形成。在此功能背景下，我们假设AD病理生理学中的早期起始事件可能在操作上涉及由全身性促炎慢性状态导致的外周和中枢组成型一氧化氮信号通路失调的汇合，并导致功能严重失调的“过度活化”小胶质细胞。
