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

阿尔茨海默病发病机制中的神经网络和免疫细胞功能障碍

• 批准号: 10077445
• 负责人: Lennart Mucke
• 金额: $ 47.25万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077445
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antiepileptic Agents; Biological Markers; Brain; Brain region; Cells; Chemicals; Cognitive deficits; Data; Development; Disease; Disease Progression; Electroencephalography; Epilepsy; Excitatory Neurotoxins; Functional disorder; Genes; Genetic; Histopathology; Human; Human Amyloid Precursor Protein; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Markers; Impaired cognition; Impairment; Inflammation Mediators; Inflammatory; Injury; Knock-in; Knock-in Mouse; Knowledge; Learning; Levetiracetam; Light; Link; Mediating; Memory; Microglia; Missense Mutation; Modeling; Molecular; Morphology; Mouse Protein; Mus; Mutation; Myeloid Cells; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Plasma; Predisposition; Prevention; Research; Research Project Summaries; Risk; Role; Seizures; Senile Plaques; Solid; Synapses; TREM2 gene; Testing; Therapeutic; Time; Transgenic Mice; Variant; abeta accumulation; base; brain abnormalities; brain cell; cytokine; density; genetic variant; genome wide association study; immune activation; improved; mouse model; network dysfunction; neural circuit; neural network; novel; novel therapeutics; peripheral blood; pre-clinical; preservation; radiological imaging; reduce symptoms; response; risk variant; synaptic function; targeted treatment; tau Proteins; transcriptome; transcriptomics

PROJECT SUMMARY 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.

项目摘要 关于阿尔茨海默氏病（AD）的研究强烈关注可检测到的病理改变 组织病理学或放射学成像，例如斑块和缠结。但是，针对这些的药物治疗 AD患者的认知能力下降并没有减慢目的地的认知能力下降。 脑。发现广告生物标志物的努力也主要集中在神经病理学改变上。到 追求新颖的方向并填补了该领域的重要知识空白，该提案在功能上着重于 相关的神经元网络异常可能是认知缺陷的基础，并且可以促进神经退行性 通过不同的机制，包括小胶质细胞功能障碍，细胞的先天免疫小细胞的功能障碍，以及AD的进展 大脑。以前，我们发现AD和相关小鼠模型患者的亚临床癫痫活性。在 患者，这种网络异常的程度预测了认知能力下降。在鼠标模型中 预防或反向网络功能障碍改善了生存率和认知缺陷。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新的致病联系。 抑制癫痫活性降低了淀粉样蛋白B（AB）水平升高的小鼠的小胶质细胞激活 脑。用小胶质细胞功能障碍的小鼠敲入小鼠，由人类免疫基因变体诱导，增加了AD 抗激毒毒素挑战后的癫痫活性增加和延长。 在大脑中积累AB的小鼠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，我们建议检验新颖和统一的假设 神经网络活动和免疫功能障碍参与了促进合成损失的美好周期 AD认知能力下降的最可能原因。可以想象，这些组件中的任何一个都可以启动周期，可能 在不同的患者的不同时间以及响应发散的触发因素，包括受伤引起的激增 淀粉样蛋白-B（AB）或TAU水平以及与衰老相关的变化。首先触发哪些组件可能取决于 关于一个人的遗传学，包括影响小胶质功能的基因。我们将使用与广告相关的鼠标模型 开始在临床前测试这些假设。具体来说，我们将确定（1）抑制 神经网络异常减少了异常小胶质激活并保留突触密度，（2）网络 功能障碍和合成缺陷反映在外周血中的免疫标记和（3）小胶质细胞 功能障碍会导致异常网络活动和突触损失。拟议的研究将有助于描述 免疫细胞在与广告相关的网络功能障碍和突触障碍中的作用。他们也可能确定 潜在的新生物标志物，例如脑电图和周围血液的改变，可以帮助识别 调节免疫细胞活动的治疗策略，这些策略最终可能使AD患者和人们受益 有患这种疾病的风险。