Plasticity and vulnerability of basal forebrain cholinergic neurons in Alzheimer's Disease

阿尔茨海默病中基底前脑胆碱能神经元的可塑性和脆弱性

• 批准号: 10057060
• 负责人: Daniel T Pak
• 金额: $ 42.9万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057060
• 关键词: Acetylcholine; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Antiepileptic Agents; Area; Atrophic; Attention; Axon; Biology; Brain; Calcium; Cell Death; Cells; Cholinergic Agents; Cholinergic Receptors; Cholinesterase Inhibitors; Coculture Techniques; Cognition; Cognitive deficits; Coupled; Dementia; Development; Disease; Disease Progression; Electrophysiology (science); Event; Financial compensation; Functional disorder; Hippocampus (Brain); Human; Hyperactive behavior; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Investigation; Knock-in; Knowledge; Lead; Link; Memory; Memory impairment; Modeling; Molecular; Morphology; Mus; Muscarinics; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Physiological; Play; Predisposition; Property; Psyche structure; Role; Senile Plaques; Structure; Synapses; Synaptic plasticity; System; Technology; Testing; age related; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; cholinergic synapse; cognitive benefits; combat; entorhinal cortex; experimental study; immunocytochemistry; improved; in vivo; innovation; innovative technologies; interdisciplinary approach; mouse model; multidisciplinary; nerve supply; neuron development; neuron loss; optogenetics; patch clamp; preservation; response; sensor; slow potential; success; symptom treatment; synaptic function; synaptogenesis; targeted treatment; tau Proteins; virtual

The profound loss of basal forebrain cholinergic neurons (BFCNs) is an early hallmark in Alzheimer’s disease (AD). As cholinergic innervation is essential for cognition, degeneration of BFCNs may be linked to mental decline in AD patients. Current AD therapies involving cholinergic drugs provide modest benefits but are not based on disease mechanisms and do not halt BFCN degeneration. The reasons for the vulnerability of BFCNs to cell death in AD are largely unknown, but BFCN loss predicts degeneration in cortex, and cholinesterase inhibitors reduce atrophy in basal forebrain as well as cortex and hippocampus. These observations support the premise that protection of BFCNs could slow pathogenesis in AD. Thus, there is an urgent need to identify molecular mechanisms of cell death in BFCNs. In this proposal, we will investigate molecular events associated with BFCN dysfunction. We focus on neuronal hyperexcitability, which is a prominent, early feature in AD patients linked to cognitive deficits. Hyperactivity induces homeostatic synaptic plasticity (HSP), a compensatory mechanism that tunes synaptic strength in response to perturbations in neuronal activity, thereby maintaining excitation within an optimal range and preserving network stability. However, little is known regarding HSP in mammalian CNS cholinergic synapses, in normal conditions or in AD models. We will test the hypothesis that hyperexcitation and HSP mechanisms exacerbate AD pathogenesis. Furthermore, we propose that BFCNs, which are highly vulnerable and affected early in AD, provide a sensitive readout for detecting such dysfunctions. We propose the following aims: 1) Using an optimized septal-hippocampal co-culture system, we will examine the course of normal BFCN and cholinergic synapse development; determine morphological and functional changes that occur in cholinergic neurons and synapses during overexcitation conditions; and utilize similar co-cultures prepared from an AD mouse model to examine the perturbations to BFCNs in their normal development, response to hyperexcitation, and susceptibility to distinct forms of cell death. 2) We will analyze BFCNs and target hippocampal neurons in vivo with multidisciplinary approaches to examine the homeostatic responses to hyperexcitation, and use ChAT-Cre mice crossed to an AD mouse model to identify impairments in BFCN structure or synaptic function, under both basal and hyperexcitation conditions. These significant studies use innovative technology to investigate questions of basic and translational importance. If successful, the findings may lead to improved therapies against BFCN neurodegeneration in AD.

基底前脑胆碱能神经元（BFCN）的严重缺失是阿尔茨海默病的早期标志 （AD）。由于胆碱能神经支配对于认知是必不可少的，BFCN的变性可能与精神疾病有关。 减少AD患者。目前涉及胆碱能药物的AD疗法提供了适度的益处， 基于疾病机制，并不能阻止BFCN的退化。BFCN脆弱性的原因 AD中的细胞死亡在很大程度上是未知的，但BFCN损失预测皮质变性， 抑制剂减少基底前脑以及皮质和海马的萎缩。这些观察结果支持了 前提是BFCN的保护可以减缓AD的发病机制。因此，迫切需要查明 BFCN细胞死亡的分子机制。在这个提议中，我们将研究与此相关的分子事件， BFCN功能障碍我们关注神经元的过度兴奋，这是AD患者的一个突出的早期特征 与认知缺陷有关过度活跃诱导稳态突触可塑性（HSP），一种代偿性突触可塑性。 调节突触强度的机制，以响应神经元活动的扰动，从而维持 在最佳范围内激励并保持网络稳定性。然而，关于HSP在 哺乳动物CNS胆碱能突触，在正常条件下或在AD模型中。我们将检验这个假设， 过度兴奋和HSP机制加重AD发病机制。此外，我们建议BFCN， 其在AD的早期是高度脆弱和受影响的，提供了用于检测这种功能障碍的灵敏读数。 我们提出以下目的：1）利用优化的隔-海马共培养体系， 正常BFCN和胆碱能突触发育的过程;确定形态和功能 在过度兴奋条件下胆碱能神经元和突触中发生的变化;并利用从AD小鼠模型制备的类似共培养物来检查BFCN在其正常发育中的扰动， 对过度兴奋的反应和对不同形式的细胞死亡的敏感性。2)我们将分析BFCN， 用多学科方法在体内靶向海马神经元， 并使用ChAT-Cre小鼠与AD小鼠模型杂交以鉴定BFCN中的损伤 结构或突触功能，在基础和过度兴奋条件下。这些重要的研究使用 创新技术，以调查基本和转化的重要性问题。如果成功， 可能导致改善AD中BFCN神经变性的治疗。