Dysfunctional homeostatic plasticity in Alzheimer's Disease

项目概要/摘要 脑功能随着阿尔茨海默病（AD）的进展而下降。观察到的大量神经元损失 在疾病的进展阶段，可以证实观察到大脑控制神经元的回路中断， 大脑的任务受到影响。然而，这在疾病的发展中为时已晚。β-淀粉样蛋白（Aβ） 多年来逐渐积累，超过疾病早期的生理水平。 不幸的是，在第一个症状出现之前，人们对Aβ的影响知之甚少。到那时， 报告说，除其他外，神经元的兴奋性增加了。我们发现大脑皮层 年轻的APPNL-G-F小鼠的锥体神经元，一种相对新颖的AD小鼠模型， 淀粉样前体蛋白，但在出生后第二个月后积极积累Aβ， 这些生理特征表明，与来自神经元的神经元相比， 年龄匹配的对照组。3-4个月后，当Aβ积累显著时，相同的指标显示 兴奋性的波动，神经元变得比对照组小鼠更兴奋， 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稳态机制。我们的假设是早期的积累 导致皮质神经元的低兴奋性，导致在晚期阶段的病理性过度兴奋。 这种疾病这种兴奋性的异常转换是体内平衡受损的结果。 CaMKIV活性上调引起的机制。现在出现的问题是Aβ 积累导致低兴奋性，是什么原因导致兴奋性在几个月后反弹，以及是否 存在一种可以纠正低兴奋状态以防止高兴奋状态的操作。回答 这些问题，我们将测试以下假设：（1）低兴奋性在年轻的APPNL-G-F小鼠引起的 通过上调电压门控钾通道、下调电压门控钠通道 变化，或两者兼而有之，（2）稳态可塑性的缺陷或饱和机制导致低兴奋性， 年龄较小，（3）稳态可塑性失调是Aβ蓄积的直接结果，（4） 在APPNL-G-F小鼠模型的病理学进展中，在青年期出现低兴奋性 是后期（中年）过度兴奋的原因，（5）早期低兴奋性导致体内平衡减弱 由于CaMKIV的下调，以及（6）使用FDA-1长期阻断K+通道， 在病理学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，临床上最相关的AD小鼠模型，体内2 PE 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。要求1 将确定机制负责早期，前斑块低兴奋性的锥体神经元在APPNL-G-F 小鼠和Aim 2将确定旨在纠正锥体神经元早期低兴奋性的干预措施是否可以 预防或减少中年过度兴奋。通过使用最先进的技术和创新 在实验和动物模型中，我们将阐明AD病理学进展对神经元的影响， 自我平衡机制这项研究有可能产生新的知识的赤字影响 在认知症状出现之前，为大脑功能设计和改善个性化或 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.