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.

项目摘要/摘要阿尔茨海默氏症患者的大脑和该疾病最好的生物标志物的首次变化是合成损失。几项研究表明，PSD-95（突触时主要的脚手架蛋白）显着耗尽在阿尔茨海默氏症患者以及暴露于淀粉样蛋白β的神经元中引起阿尔茨海默氏病（AD）。我们的数据表明，升高的PSD-95阻断Aβ诱导的突触沮丧。令人惊讶的是，这种作用似乎与突触潜力无关，但要受到PSD的干扰 NMDA接收器信号传导的95。此外，我们观察到，大树突状刺，包含许多PSD-95，不受Aβ的影响和较小的棘突（PSD-95）更脆弱。表明内源性PSD-95也受到保护。这些发现表明，突触PSD- 95保护突触免受Aβ的影响。突触PSD-95的量由一个称为的过程控制介导PSD-95在突触后膜中插入的“棕榈酰化”。特定酶最近确定了从突触中去除PSD-95的PSD-95 depalmitoylation。这因此，该提案的重点是测试新型药物靶标的潜力PSD-95 depalmitoylating 酶，作为针对阿尔茨海默氏症的新治疗途径。我们的初步体外和体内结果，使用该酶的商业可用抑制剂（palesment b）非常有前途。体外实验表明该药物可以挽救Aβ诱导的突触抑制和Aβ介导的对树突状的影响刺。我们建议在AD中研究疾病中对大脑区域的PSD-95棕榈酰化模型小鼠（APP/PS1）和尸体后人脑样品。这些实验可以解释为什么大脑区域（和个人）更容易受到广告的影响。在App/PS1小鼠中，PSD-95棕榈酰化海马大大低于WT同窝仔，而总PSD-95水平几乎没有影响。这表明PSD-95棕榈酰化的丧失将在PSD-95减少之前发生。重要的是，腹膜内腔中的最触觉t的注射剂以剂量依赖性的方式恢复了这种作用，表明该药物可以在体内进入大脑突触。在这个项目中，我们将研究功能该救援和测试是否在这些应用程序/PS1小鼠中观察到的定义的后果可以通过增加突触PSD-95。我们预计抑制PSD-95 depalmitoylation将提高性能这些AD模型小鼠中涉及记忆和救助突触生理障碍的行为测试。总体而言，这个创新的项目将以不同大脑区域的PSD-95贩运来表征 PSD-95 depalmitoylating酶的药理阻滞可以在APP/PS1模型小鼠中挽救防御。最后，增加突触PSD-95应该使脆弱的突触更强，这对既可以治疗和预防广告。