Neural network and immune cell dysfunctions in Alzheimer's disease pathogenesis

对阿尔茨海默病（AD）的研究主要集中在通过免疫组织化学检测的病理改变上。 组织病理学或放射成像，如斑块和缠结。然而，针对这些疾病的药物治疗 尽管有明确的证据表明靶点参与了AD患者的认知能力下降，但这些改变并没有减缓AD患者的认知能力下降。 个脑袋发现AD生物标志物的努力也主要集中在神经病理学改变上。到 追求新的方向，并填补该领域的重要知识空白，该提案侧重于功能 相关的神经网络异常，可能是认知缺陷的基础，并可能促进神经退行性变 和AD的进展通过不同的机制，包括功能障碍的小胶质细胞，先天性免疫细胞， 大脑以前，我们在AD患者和相关小鼠模型中发现了亚临床癫痫活动。在 在病人中，这种网络异常的程度预示着认知能力的下降。在小鼠模型中， 网络功能障碍的预防或逆转改善了存活率并减少了认知缺陷。最近 获得的初步数据表明，网络和免疫细胞功能障碍之间存在一种新的致病联系。 抑制癫痫活动减少了小鼠中淀粉样蛋白b（Ab）水平升高的小胶质细胞活化， 个脑袋由增加AD的人类免疫基因变体诱导的小胶质细胞功能障碍的敲入小鼠 风险，增加和延长癫痫活动后的挑战与兴奋毒素。非惊厥性癫痫 在Ab在脑中蓄积的小鼠中的活性与特定炎症介质的水平相关， 等离子体基于这些有趣的发现，我们建议测试新的和统一的假设， 神经网络活动和免疫功能障碍参与促进突触丧失的恶性循环， 最有可能导致AD认知能力下降的原因可以想象，这两种成分中的任何一种都可能启动循环， 在不同的时间，在不同的病人，并响应于不同的触发，包括损伤引起的激增， 淀粉样蛋白-b（Ab）或tau水平和衰老相关的改变。哪个组件首先被触发可能取决于 包括影响小胶质细胞功能的基因。我们将使用AD相关的小鼠模型， 开始在临床前水平上检验这些假设。具体而言，我们将确定（1）抑制 神经网络异常减少异常的小胶质细胞激活并保持突触密度，（2）网络 功能障碍和突触缺陷由外周血中的免疫标记物反映，和（3）小胶质细胞 功能障碍导致异常的网络活动和突触损失。拟议的研究将有助于界定 免疫细胞在AD相关网络功能障碍和突触损伤中的作用。他们也可以识别 潜在的新生物标志物，如EEG特征和外周血改变，并可以帮助识别 调节免疫细胞活性的治疗策略，最终可能使AD患者和人类受益 有患上这种疾病的风险

Research on Alzheimer’s disease (AD) has strongly focused on pathological alterations detectable by histopathology or radiological imaging such as plaques and tangles. However, drug treatments targeting these alterations have not slowed cognitive decline in AD patients despite clear evidence for target engagement in the brain. Efforts to discover biomarkers for AD have also focused primarily on neuropathological alterations. To pursue novel directions and fill important knowledge gaps in the field, this proposal focuses on functionally relevant neural network abnormalities that likely underlie cognitive deficits and could promote neurodegeneration and AD progression through diverse mechanisms, including dysfunction of microglia, the innate immune cells of the brain. Previously, we found subclinical epileptic activity in patients with AD and in related mouse models. In the patients, the extent of such network abnormalities predicted cognitive decline. In the mouse models, prevention or reversal of the network dysfunction improved survival and reduced cognitive deficits. More recently obtained preliminary data suggest a novel pathogenic link between network and immune cell dysfunction. Suppressing epileptic activity reduced microglial activation in mice with elevated amyloid-b (Ab) levels in the brain. Knock-in mice with microglial dysfunction, induced by a human immune gene variant that increases AD risk, had increased and prolonged epileptic activity after challenge with an excitotoxin. Nonconvulsive epileptic activity in mice with Ab accumulation in the brain correlated with levels of specific inflammatory mediators in plasma. Based on these intriguing findings, we propose to test the novel and unifying hypothesis that aberrant neural network activity and immune dysfunction engage in a vicious cycle that promotes synaptic loss, the likeliest cause of cognitive decline in AD. Conceivably, either of these components can initiate the cycle, possibly at different times in different patients and in response to diverse triggers, including injury-induced surges in amyloid-b (Ab) or tau levels and aging-related alterations. Which of the components is triggered first may depend on a person’s genetics, including genes affecting microglial functions. We will use AD-related mouse models to begin to test these hypotheses at the preclinical level. Specifically, we will determine whether (1) suppression of neural network abnormalities reduces aberrant microglial activation and preserves synaptic density, (2) network dysfunction and synaptic deficits are reflected by immune markers in peripheral blood, and (3) microglial dysfunction contributes to aberrant network activity and synaptic loss. The proposed studies will help delineate the role of immune cells in AD-related network dysfunction and synaptic impairment. They may also identify potential new biomarkers, such as EEG signatures and peripheral blood alterations, and could help identify therapeutic strategies to modulate immune cell activities that may ultimately benefit patients with AD and people at risk of developing this disorder.