Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease.
Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease.
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DOI：
10.3233/jad-142853
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Harris EA
中科院分区：
文献类型：
--
作者：
Harris SA;Harris EA
本文从流行病学、神经病理学、分子生物学和遗传学等方面对病原体与易感基因相互作用在散发性阿尔茨海默病(AD)发病机制中的作用作一综述。散发性阿尔茨海默病是一种复杂的多因素神经退行性疾病，有证据表明多种病因和炎性病因并存。AD与多种病原体有关，包括单纯疱疹病毒1型(HSV-1)、巨细胞病毒和其他疱疹病毒科、肺炎衣原体、螺旋体、幽门螺杆菌和各种牙周病原体。这些病原体能够逃避宿主免疫系统的破坏，导致持续感染。细菌和病毒的DNA和RNA以及细菌配体增加了促炎分子的表达，并激活了先天和获得性免疫系统。有证据表明，病原体直接或间接诱导AD病理，包括淀粉样蛋白(Aβ，Aβ)蓄积、tau蛋白磷酸化、神经元损伤和细胞凋亡。慢性脑感染HSV-1、肺炎衣原体和螺旋体导致复杂的过程，这些过程相互作用，导致无法控制的神经炎症和神经退化的恶性循环。巨细胞病毒、幽门螺杆菌和牙周病原体等感染可诱导全身性促炎细胞因子的产生，这些细胞因子可能会越过血脑屏障促进神经退化。病原体诱导的炎症和中枢神经系统中Aβ的蓄积破坏了血脑屏障，参与了AD的病理生理过程。载脂蛋白E4(ApoE4)可促进HSV-1和肺炎衣原体等病原体对脑的侵袭。载脂蛋白E4还与免疫系统增加的促炎反应有关。潜在的抗菌治疗AD的讨论，包括抗病毒和抗生素临床试验的基本原理。
This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.