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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.

项目总结/摘要阿尔茨海默氏症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丢失。几项研究表明，PSD-95（突触处的主要支架蛋白）显著减少，在阿尔茨海默氏症患者的脑组织以及暴露于β淀粉样蛋白（Aβ，一种被认为是导致阿尔茨海默病（AD））。我们的数据表明，PSD-95的升高阻断了Aβ诱导的突触萧条令人惊讶的是，这种效应似乎不依赖于突触增强，而是受到PSD的干扰。 95的NMDA受体信号。此外，我们观察到含有大量PSD-95的大树突棘，不受Aβ的影响，较小的脊柱，PSD-95含量较低，更容易受到影响; 提示内源性PSD-95也具有保护作用。这些发现表明，增加突触PSD- 95保护突触免受Aβ的侵害。突触PSD-95的数量由一个称为 “棕榈酰化”介导PSD-95插入突触后膜。酶比负责PSD-95去棕榈酰化，从突触中除去PSD-95。的因此，该提案的重点是测试一种新的药物靶点PSD-95去棕榈酰化的潜力酶，作为一种新的治疗手段，对阿尔茨海默氏症。我们的初步体外和体内结果，使用市售酶抑制剂（Palmostatin B）是非常有前途的。体外实验结果表明，该药物可以挽救Aβ诱导的突触抑制和Aβ介导的树突状细胞的作用，刺我们建议研究PSD-95棕榈酰化在大脑区域不同影响的疾病在AD 模型小鼠（APP/PS1）和死后人脑样品。这些实验可以解释为什么某些大脑区域（和个体）更容易受到AD的影响。在APP/PS1小鼠中，海马体显著低于WT同窝仔，而总PSD-95水平几乎不受影响。这表明PSD-95棕榈酰化的损失将在PSD-95减少之前发生。重要的是，在腹腔内注射帕莫司他丁B以剂量依赖性方式挽救了该效应，表明这种药物可以在体内进入大脑突触。在这个项目中，我们将研究功能拯救的结果和测试在这些APP/PS1小鼠中观察到的缺陷是否可以通过增加突触PSD-95我们预期抑制PSD-95去棕榈酰化将改善在药物治疗中的性能。行为测试涉及这些AD模型小鼠中的记忆和拯救突触生理学损伤。总体而言，这个创新项目将描述PSD-95在不同大脑区域的贩运特征，并测试是否 PSD-95去棕榈酰化酶的药理学阻断可以挽救APP/PS1模型小鼠中的缺陷。最后，增加突触PSD-95应该使脆弱的突触更强大，这将有利于治疗和预防AD。