Microbes and the ageing brain: do host-microbe interactions accelerate age-related cognitive decline?

原理：大脑老化的一个标志是淀粉样蛋白β（ABeta）的沉积。患有慢性微生物感染的老年人具有较高的淀粉样蛋白负荷和患痴呆症的风险增加，但其潜在机制尚不清楚。ABeta肽与抗菌肽具有相同的生理生化活性.例如，ABeta保护培养的细胞免受致命的酵母和细菌感染，并在ABeta原纤化过程中隔离病原体。我们假设病原体介导的ABeta纤维化是先天免疫反应的一部分，其在衰老过程中经历慢性激活，导致过量的ABeta沉积和神经功能障碍，最终导致痴呆。使用的方法：我们将使用体内模型（小鼠和C. elegans），以测试微生物感染如鼠伤寒沙门氏菌，白色念珠菌和牙龈卟啉单胞菌如何影响健康衰老，通过执行一系列行为，生理和细胞测定，包括神经元功能，肠道通透性，微生物组组成和免疫反应。学生将有机会获得转基因模型，以测试微生物感染加速老化过程中存在的人类淀粉样蛋白聚集的假设。学生还将使用一系列药理学和/或饮食方法来干扰宿主-微生物相互作用，以促进健康衰老和延迟神经元功能障碍。这些干预措施将在C.并在小鼠模型中得到证实。影响领域：考虑到微生物病原体和脑功能障碍之间的密切联系以及痴呆症的抗菌假说的出现，这种学生身份可能会提供急需的深入了解与微生物病原体相关的神经退行性变的机制。建立微生物病原体影响大脑内外神经元的机制可能会为未来的转化研究提供信息，包括发现旨在调节痴呆症中病原体相关网络和分子的候选疗法。

Rationale: A hallmark of the aging brain is the deposition of amyloid-Beta (ABeta). Elderly with chronic microbial infections have a higher amyloid load and an increased risk of developing dementia, but the underlying mechanism(s) are not known. ABeta -peptides share physiochemical and biological activities with antimicrobial peptides. For example, ABeta protects cultured cells against lethal yeast and bacterial infections, and sequesters pathogens during the process of ABeta fibrilization. We hypothesize that pathogen-mediated ABeta fibrilization is part of the innate immune response, which undergoes chronic activation during aging leading to excessive ABeta deposition and neural dysfunction that eventually results in dementia. Approaches to be used: We will use in vivo models (mouse and C. elegans), to test how microbial infections such as Salmonella Typhimurium, Candida albicans and Porphyromonas gingivalis affect healthy ageing, by performing an array of behavioural, physiological and cellular assays, including neuronal function, gut permeability, microbiome composition and immune responses. The student will have access to transgenic models to test the hypothesis that microbial infections accelerate the ageing process in the presence of aggregated human amyloid. The student will also use a range of pharmacological and/or dietary approaches, to interfere with host-microbe interaction with the aim to promote healthy ageing and delay neuronal dysfunction. These interventions will be tested in C. elegans and confirmed in mouse models. Areas of impact: Taking into consideration the strong links between microbial pathogens and brain dysfunction and the emergence of the antimicrobial hypothesis of dementia, this studentship may provide much needed insight into the mechanisms underpinning neurodegeneration associated with microbial pathogens. Establishing the mechanisms by which microbial pathogens impact on the neurons in or outside the brain, may inform aspects of future translational studies, including discovery of candidate therapeutics aimed at regulating pathogen-associated networks and molecules in dementia.