Innate immune dysregulation in Alzheimer's disease modeled in Drosophila

摘要 我们认为tau调节大脑中的先天免疫和AMP，从而促进 阿尔茨海默氏症。我们将用果蝇来测试这个想法，在果蝇中，tau的失调是由人类产生的 与神经退化相关的突变引入果蝇的内源性tau，以及由经典的tau过度- 表情。在这两种模型中，tau调节失调都会导致运动和嗅觉随年龄增长而下降。Tau Over- 表达产生神经病理，我们将在新的tau突变模型中评估这些特征。我们的核心是 我们发现，在tau突变模型中，先天免疫的基因表达发生了显著的变化。 先天免疫表达增强是衰老果蝇的一个共同特征，数据表明它在其中起作用 会导致死亡，也可能会导致神经退化。根据我们的观察，我们认为tau的失调驱动了 衰老果蝇大脑中的先天免疫AMPs达到致病水平，导致年龄依赖 神经退行性变。在这一观点中，类似的过程很可能发生在人类身上，驱动抗体的积累。如果是的话， AD可能是通过什么驱动、调节和失调老化大脑中的先天免疫来管理的

Summary We propose that tau modulates innate immunity and AMPs in the brain, and thereby contributes to progression of Alzheimer’s disease. We will test this idea with Drosophila, where tau dysregulation is produced by a human neurodegeneration-associated mutation introduced into the fly’s endogenous tau, as well as by classic tau over- expression. In both models, tau dysregulation causes age-dependent decline in locomotion and olfaction. Tau over- expression produces neuropathology, and we will assess these traits in our new tau-mutant model. Central to our proposal, we find that expression of genes for innate immunity are dramatically altered in the tau-mutant model. Elevated innate immune expression is a common feature of aging Drosophila, where data demonstrates it contributes to mortality and, potentially, to neurodegeneration. With our observations, we propose that tau dysregulation drives innate immune AMPs to a pathogenic level in the brain of aging Drosophila, causing age-dependent neurodegeneration. In this view, a similar process may well occur in humans that drives the accumulation of Ab. If so, AD might be managed in terms of what drives, regulates and dysregulates innate immunity in the aging brain