Increasing synaptic PSD-95, a neuroprotection approach against Alzheimer's disease

增加突触 PSD-95，一种针对阿尔茨海默病的神经保护方法

基本信息

批准号：
10212079
负责人：
Kim Bohemie Dore
金额：
$ 140.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212079
关键词：
APP-PS1 Acute Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Autopsy Behavioral Assay Biochemical Biochemical Genetics Biological Assay Biological Markers Brain Brain region Cells Characteristics Chemicals Chemosensitization Chiroptera Data Dendritic Spines Development Disease Disease Progression Dose Electrophysiology (science)Enzyme Inhibitor Drugs Enzymes Event Exposure to Glutamate Receptor Grant Hippocampus (Brain)Human Immunohistochemistry Impairment In Vitro Individual Injections Intervention Intraperitoneal Injections Knockout Mice Long-Term Potentiation Measures Mediating Memory Memory impairment Molecular Mus N-Methyl-D-Aspartate Receptors Neurons Pathologic Pathway interactions Patients Peptides Performance Pharmaceutical Preparations Pharmacology Physiological Physiology Process Proteins Proteome Receptor Signaling Sampling Scaffolding Protein Slice Specificity Synapses Synaptic Membranes Testing Therapeutic Translational Research Vertebral column base behavior test brain tissue density efficacy testing experimental study fluorescence imaging improved in vivo inhibitor/antagonist innovation intraperitoneal mouse model neuroprotection new therapeutic target normal aging novel novel therapeutics palmitoylation prevent synaptic depression trafficking translational approach

项目摘要

Project Summary/Abstract The first change in the brains of Alzheimer’s patients and the best biomarker of the disease is synaptic loss. Several studies have shown that PSD-95 (a major scaffolding protein at the synapse) is significantly depleted in brain tissue of Alzheimer’s patients as well as in neurons exposed to amyloid beta (Aβ, a peptide thought to cause Alzheimer’s disease (AD)). Our data indicate that elevated PSD-95 blocks Aβ-induced synaptic depression. Surprisingly, this effect appears independent of synaptic potentiation, but to interference by PSD- 95 of NMDA receptor signaling. Moreover, we observed that big dendritic spines, containing a lot of PSD-95, were unaffected by Aβ and that smaller spines, with lower amounts of PSD-95 were more vulnerable; suggesting that endogenous PSD-95 is also protective. These findings indicate that increased synaptic PSD- 95 protects synapses from Aβ. The amount of synaptic PSD-95 is controlled by a process called ‘palmitoylation’ which mediate the insertion of PSD-95 in post-synaptic membranes. The specific enzyme responsible for PSD-95 depalmitoylation, which removes PSD-95 from synapses, was recently identified. The key focus of this proposal is thus to test the potential of a novel drug target, PSD-95 depalmitoylating enzyme, as a new therapeutic avenue against Alzheimer’s. Our preliminary in vitro and in vivo results, using a commercially available inhibitor of that enzyme (Palmostatin B), are very promising. In vitro experiments showed that this drug could rescue Aβ-induced synaptic depression and Aβ-mediated effects on dendritic spines. We propose to study PSD-95 palmitoylation in brain regions differently affected in the disease in AD model mice (APP/PS1) and postmortem human brain samples. These experiments could explain why certain brain regions (and individuals) are more vulnerable to AD. In APP/PS1 mice, PSD-95 palmitoylation in the hippocampus was drastically lower than in WT littermates while total PSD-95 levels were barely affected. This suggests that loss of PSD-95 palmitoylation would happen before reductions in PSD-95. Importantly, Palmostatin B injections in the intraperitoneal cavity rescued that effect in a dose dependent manner, which indicates that this drug can access brain synapses in vivo. In this project, we will investigate the functional consequences of that rescue and test if deficits observed in these APP/PS1 mice can be ameliorated by increasing synaptic PSD-95. We expect that inhibiting PSD-95 depalmitoylation will improve performance in behavioral tests involving memory and rescue synaptic physiology impairments in these AD model mice. Overall, this innovative project will characterize PSD-95 trafficking in different brain regions and test if pharmacological blockade of PSD-95 depalmitoylating enzyme can rescue deficits in APP/PS1 model mice. Finally, increasing synaptic PSD-95 should make vulnerable synapses stronger, which would be beneficial for both treating and preventing AD.

项目概要/摘要阿尔茨海默病患者大脑的第一个变化和该疾病的最佳生物标志物是突触丧失。多项研究表明 PSD-95（突触的主要支架蛋白）显着耗尽阿尔茨海默病患者的脑组织以及暴露于β淀粉样蛋白（Aβ，一种被认为是一种肽）的神经元中导致阿尔茨海默病 (AD)）。我们的数据表明，升高的 PSD-95 会阻断 Aβ 诱导的突触。令人惊讶的是，这种效应似乎与突触增强无关，但与 PSD- 的干扰无关。 NMDA 受体信号传导的 95 此外，我们观察到含有大量 PSD-95 的大树突棘，不受 Aβ 的影响，并且 PSD-95 含量较低的较小的刺更容易受到伤害；表明内源性 PSD-95 也具有保护作用。这些发现表明突触 PSD- 的增加。 95 保护突触免受 Aβ 的侵害突触 PSD-95 的数量由一个称为 Aβ 的过程控制。 “棕榈酰化”介导 PSD-95 在突触后膜中的插入。最近鉴定出负责 PSD-95 去棕榈酰化，从而从突触中去除 PSD-95。因此，该提案的重点是测试新药物靶点 PSD-95 去棕榈酰化的潜力酶作为治疗阿尔茨海默病的新途径，我们使用了初步的体外和体内结果。该酶的市售抑制剂（Palmostatin B）在体外实验中非常有前景。表明该药物可以挽救 Aβ 诱导的突触抑制和 Aβ 介导的树突效应我们建议研究 AD 疾病中不同受影响的大脑区域中的 PSD-95 棕榈酰化。模型小鼠（APP/PS1）和死后人类大脑样本这些实验可以解释为什么某些。在 APP/PS1 小鼠的大脑区域（和个体）中，PSD-95 棕榈酰化更容易受到 AD 的影响。海马体的水平显着低于 WT 同窝小鼠，而总 PSD-95 水平几乎不受影响。这表明 PSD-95 棕榈酰化的丧失会发生在 PSD-95 减少之前。腹膜内注射棕榈抑素 B 以剂量依赖性方式挽救了这种作用，表明这种药物可以在体内进入大脑突触，在这个项目中，我们将研究其功能。救援的后果并测试在这些 APP/PS1 小鼠中观察到的缺陷是否可以通过以下方式改善我们预计抑制 PSD-95 去棕榈酰化将提高突触 PSD-95 的性能。行为测试涉及记忆和挽救这些 AD 模型小鼠的突触生理学损伤。总的来说，这个创新项目将描述不同大脑区域的 PSD-95 贩运特征，并测试是否 PSD-95 去棕榈酰酶的药理学阻断可以挽救 APP/PS1 模型小鼠的缺陷。最后，增加突触 PSD-95 应该会使脆弱的突触变得更强，这将有利于既能治疗又能预防AD。