Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Prog Mol Biol Transl Sci. 2019;168:147-181. doi: 10.1016/bs.pmbts.2019.06.013. Epub 2019 Jul 4.
The amyloid hypothesis of Alzheimer's disease (AD) has become outdated as researchers and clinicians recognize that lifestyle factors and environmental stressors have a greater impact on the etiology of AD than genetic predispositions. When persistent over decades, chronic psychological and physical stressors disrupt the body's natural adaptions to stress (allostasis) resulting in a general "wear and tear" on the body termed allostatic overload. Allostatic overload results in hypercortisolemia, disrupted hypothalamic-pituitary-adrenal (HPA) axis regulation, elevated proinflammatory cytokines and chemokines, reduced synaptic plasticity, persistently activated microglia, and importantly, a dysbiotic gut microbiota. This plethora of physiological maladaptations precedes the canonical symptoms of AD, including amyloid-beta plaque accumulation and tau hyperphosphorylation, indicating that a successful therapeutic approach to AD must first alleviate these risk factors. In this chapter, the use of gut microbiota modifying synbiotics, a combination of probiotics and prebiotics, to simultaneously and sustainably alleviate stress-induced AD risk factors is proposed. Synbiotic-derived bioactive metabolites can increase the integrity of the gut epithelial barrier preventing the infiltration of bacterial peptides and other immune-activating substances. These metabolites can also alter the balance of peripheral immune cells toward an anti-inflammatory state, protecting the body against stress-induced inflammatory challenges. These peripheral adaptations ultimately promote cognitive resilience to stress-induced AD by preventing microglia inflammasome activation, reinstating HPA axis negative feedback loops and allowing healthy neurogenic and neuroplasticity processes to ensue. Overall, synbiotics provide a novel treatment paradigm for AD that promote a sustainable allostasis to chronic stress, protecting the brain from the neuropathologies driving AD.
阿尔茨海默病（AD）的淀粉样蛋白假说已经过时，因为研究人员和临床医生认识到，生活方式因素和环境应激源对 AD 的病因学的影响大于遗传易感性。当持续数十年时，慢性心理和身体应激源会破坏身体对压力的自然适应（体内平衡），导致身体的普遍“磨损”，称为适应负荷过载。适应负荷过载导致皮质醇过多、下丘脑-垂体-肾上腺（HPA）轴调节紊乱、促炎细胞因子和趋化因子升高、突触可塑性降低、持续激活的小胶质细胞，重要的是，肠道微生物群落失调。这些大量的生理适应不良先于 AD 的典型症状，包括淀粉样蛋白-β斑块积累和 tau 过度磷酸化，这表明成功的 AD 治疗方法必须首先减轻这些风险因素。在这一章中，提出了使用肠道微生物群修饰共生体（益生菌和益生元的组合）来同时和可持续地减轻应激诱导的 AD 风险因素。共生体衍生的生物活性代谢物可以增加肠道上皮屏障的完整性，防止细菌肽和其他免疫激活物质的渗透。这些代谢物还可以改变外周免疫细胞的平衡，使其向抗炎状态转变，使身体免受应激诱导的炎症挑战。这些外周适应最终通过防止小胶质细胞炎症小体激活、恢复 HPA 轴负反馈回路并允许健康的神经发生和神经可塑性过程发生，促进对应激诱导的 AD 的认知弹性。总的来说，共生体为 AD 提供了一种新的治疗模式，促进了对慢性应激的可持续体内平衡，保护大脑免受驱动 AD 的神经病理学影响。
