Dysfunctional homeostatic plasticity in Alzheimer's Disease

项目摘要/摘要 随着阿尔茨海默病(AD)的发展，大脑功能会下降。观察到神经元的大量丢失 在疾病的进展阶段，对大脑控制回路的破坏进行了确凿的观察 大脑任务受到了影响。然而，这在疾病的发展过程中为时已晚。β-淀粉样蛋白(A-β) 在多年后逐渐积累，超过了疾病早期的生理水平。 不幸的是，在最初的症状出现之前，人们对β的影响知之甚少。到那时，它已经是 据报道，除其他外，神经元的兴奋性增加。我们发现了大脑皮层 幼年APPNL-G-F小鼠的锥体神经元--一种相对新的不过度表达的AD小鼠模型 淀粉样前体蛋白，但在生命第二个月后积极积累Aβ，目前存在 这些生理特征表明，与来自 年龄匹配的对照组。同样的指标在3-4个月后，当Aβ积累显著时，显示 它们的兴奋性的波动，神经元变得比对照组更兴奋，导致更多的 与文献中的数据一致。我们认为，持续的低兴奋性会导致 6月龄小鼠内在兴奋性的动态平衡机制。我们的假设是早期积累 Aβ导致皮层神经元兴奋性低下，导致病理性高兴奋性。 这种疾病。兴奋性的异常转换是体内平衡受损的结果。 CaMKIV活性上调的机制。现在出现的问题是β有多早 积累会导致兴奋性低下，是什么导致了几个月后兴奋性的反弹，以及 有一种操作可以纠正低兴奋状态，以防止过度兴奋状态。回答 这些问题我们将检验以下假设：(1)幼年APPNL-G-F小鼠出现兴奋性减退 上调电压门控性钾通道，下调电压门控性钠通道 改变，或两者兼而有之，(2)体内平衡可塑性的缺陷或饱和机制在以下方面导致兴奋性低下 年轻人，(3)体内平衡可塑性失调是Aβ积聚的直接结果，(4) APPNL-G-F小鼠模型在成年期的低兴奋性在病理进展中的作用 是晚期(中年)高兴奋性的原因，(5)早期低兴奋性导致迟钝的内环境平衡 中年时的反应，由于CaMKIV下调，以及(6)长期使用FDA-K通道阻断 在病理的早期阶段批准的药物将增加兴奋性的稳态下调。我们 将使用APP敲入(APPNL-G-F)转基因小鼠，最具临床相关性的AD小鼠模型，体内2PE 显微镜、光遗传学、化学遗传学和电生理记录来验证我们的假设。目标1 将确定APPNL-G-F区锥体神经元早期、斑块前低兴奋性的机制 小鼠和Aim 2将确定旨在纠正锥体神经元早期兴奋性低下的干预措施是否可以 防止或减少中年过度兴奋。使用最先进的技术和创新 实验和动物模型，我们将阐明AD病理进展对神经元的影响 动态平衡机制。这项研究有可能产生关于赤字影响的新知识 大脑功能在认知症状出现前的个性化设计与改进 精确干预旨在预防或延迟阿尔茨海默病患者的认知障碍。

PROJECT SUMMARY/ABSTRACT Brain performance declines with Alzheimer’s disease (AD) progression. The massive loss of neurons observed at advances stages of the disease are confirmatory observations of the disruption of the brain circuits governing the brain tasks affected. This is, however, too late in the progression of the disease. Beta-amyloid (Aβ) progressively accumulates over many years, surpassing its physiological levels early in the disease. Unfortunately, little is known about the effects of Aβ before the first symptoms appear. By then, it has been reported, among other things, that there is an increase in the excitability of the neurons. We found that cortical pyramidal neurons of young APPNL-G-F mice, a relatively novel mouse model of AD that does not overexpress amyloid precursor protein, but accumulates Aβ aggressively after the second month of life, present with physiological features that indicate a reduction of their intrinsic excitability when compared with neurons from age-matched controls. The same indicators 3-4 months later, when the accumulation of Aβ is significant, show a swing in their excitability, and the neurons become more excitable than in control mice, results more in agreement with the data from the literature. We believe that sustained hypoexcitability results in impaired homeostatic mechanisms of intrinsic excitability in 6-month-old mice. Our hypothesis is that early accumulation of Aβ leads to hypoexcitability of cortical neurons resulting in a pathological hyperexcitability at later stages of the disease. This abnormal switch in excitability is a consequence of an impairment of the homeostatic mechanism caused by upregulation of CaMKIV activity. The questions that arise now are how early Aβ accumulation leads to hypoexcitability, what causes the rebound in excitability a few months later, and whether there is a manipulation that could correct the hypoexcitable state to prevent the hyperexcitable state. To answer these questions we will test the following hypotheses: (1) hypoexcitability in the young APPNL-G-F mice is caused by upregulation of voltage-gated potassium channels, downregulation of voltage-gated sodium channels changes, or both, (2) defective or saturated mechanisms of homeostatic plasticity lead to hypoexcitability at younger ages, (3) homeostatic plasticity dysregulation is a direct consequence of Aβ accumulation, (4) hypoexcitability occurring during young adulthood in the progression of pathology in the APPNL-G-F mouse model is a cause of hyperexcitability at later stages (middle age), (5) early hypoexcitability results in blunted homeostatic response at middle age, due to downregulation of CaMKIV, and (6) long-term block of K+ channels using FDA- approved drugs during early stages of the pathology will increase homeostatic downregulation of excitability. We will use APP knock-in (APPNL-G-F) transgenic mice, the most clinically relevant mouse model of AD, in vivo 2PE microscopy, optogenetics, chemogenetics, and electrophysiological recordings to test our hypotheses. Aim 1 will identify the mechanisms responsible for early, pre-plaque hypoexcitability of pyramidal neurons in APPNL-G-F mice and Aim 2 will determine if interventions aimed to correct early hypoexcitability of pyramidal neurons can prevent or decrease middle age hyperexcitability. By using state of the art techniques and innovative experimental and animal models, we will elucidate the effects of the progression of the AD pathology on neuronal homeostatic mechanisms. This study has the potential to generate novel knowledge on the deficits impacting brain function before the appearance of cognitive symptoms for the design and improvement of personalized or precision interventions aimed to prevent or delay cognitive disturbances in Alzheimer’s disease patients.