Assessing the effects of Synj1 haploinsufficiency in Alzheimer's disease models

评估 Synj1 单倍体不足对阿尔茨海默病模型的影响

• 批准号: 7658997
• 负责人: Gilbert Di Paolo
• 金额: $ 7.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658997
• 关键词: Actins; Acute; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Animals; Behavioral; Bilateral; Biochemical; Brain; Calcium; Cannulas; Catabolism; Cell Survival; Cell membrane; Cell surface; Cells; Cerebrum; Chronic; Cognitive deficits; Collaborations; Data; Defect; Dementia; Dendritic Spines; Development; Disease; Disease Progression; Dorsal; Down-Regulation; Electrophysiology (science); Exhibits; Functional disorder; Genes; Genetic Models; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Homeostasis; Impaired cognition; Individual; Injection of therapeutic agent; Ion Channel; Learning; Link; Lipids; Long-Term Potentiation; Measurement; Mediating; Membrane Protein Traffic; Memory; Memory impairment; Metabolism; Mus; Mutation; NMDA receptor antagonist; Neurons; Pathogenesis; Pathway interactions; Patients; Peptides; Performance; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Phosphoric Monoester Hydrolases; Preparation; Presenile Alzheimer Dementia; Process; Radial; Relative (related person); Research Personnel; Role; Sampling; Senile Plaques; Short-Term Memory; Signal Transduction; Slice; Synapses; Synaptic plasticity; Testing; Transgenic Mice; Upper arm; Water; Wild Type Mouse; abeta oligomer; age related; behavior test; conditioned fear; extracellular; familial Alzheimer disease; in vivo; morris water maze; mouse model; mutant; neurobehavioral; neurotoxic; novel; phosphatidylinositol phosphate, PtdIns(4,5)P2; presenilin-1; prevent; protein aggregate; public health relevance; research study; synaptojanin

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of late-onset dementia. Growing evidence suggests that cerebral elevation and accumulation of amyloid-beta peptide (Abeta) mediate many aspects of the disease's pathogenesis. While brains from AD patients generally contain amyloid plaques that consist of insoluble aggregates of Abeta, the levels of the soluble oligomeric forms of Abeta better correlate with cognitive decline and/or disease progression in animal models and individuals with AD. Accordingly, Abeta oligomers have been recently shown to cause synaptic defects in the hippocampus, at least in part through their ability to modulate cell surface levels of glutamate receptor-channels, actin dynamics and calcium homeostasis. Recently, we have investigated the relationship between Abeta and phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], a key signaling phospholipid that is concentrated at the plasma membrane where it controls multiple processes. We have found that treatment of primary cortical neurons with soluble Abeta oligomers significantly decreases PtdIns(4,5)P2 levels without marked effects on cell viability. PtdIns(4,5)P2 downregulation is reversible, requires extracellular Ca2+ and is partially blocked by glutamate (NMDA) receptor antagonists. To test for the relevance of this phenomenon in the synapse-impairing actions of Abeta, we have utilized a mouse genetic model in which the main pathway leading to the elimination of PtdIns(4,5)P2 at synapses has been targeted. These mice lack one copy of Synj1, a gene encoding the PtdIns(4,5)P2 phosphatase synaptojanin 1. We have found that Abeta oligomers fail to downregulate PtdIns(4,5)P2 in cultured neurons derived from Synj1+/- mice. Furthermore, the inhibitory effect of Abeta on hippocampal long-term potentiation is strongly suppressed in slices from Synj1+/- mice. Altogether, our findings suggest a novel hypothesis whereby PtdIns(4,5)P2 dyshomeostasis may underlie major early neurotoxic effects of Abeta at synapses and that Synj1 haploinsufficiency may confer protection against the actions of this peptide. While our biochemical and electrophysiology data from neuronal cultures and slice preparations point to a central role of PtdIns(4,5)P2 in Abeta-induced synaptic dysfunction, a fundamental question is whether this phenomenon is relevant for the pathophysiology of AD and, in particular, for the cognitive decline associated with this disorder. To begin to address this issue and validate our hypothesis in vivo, we plan to test whether Synj1 haploinsufficiency confers neurobehavioral benefits in animal models for AD. More specifically, we will generate double transgenic mice expressing familial AD-linked mutant versions of APP and presenilin 1 ("PSAPP mice") that are haploinsufficient for Synj1 and test whether these animals exhibit reduced age-dependent cognitive deficits relative to PSAPP mice using tests, such as fear conditioning, the radial-arm water maze and the Morris water maze. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common form of late-onset dementia. Growing evidence suggests that cerebral elevation and accumulation of amyloid-beta peptide (Abeta) mediate many aspects of the disease's pathogenesis. Recently, we have found that Abeta decreases the levels of phosphatidylinositol-4,5- bisphosphate [PtdIns(4,5)P2], a major bioactive intracellular lipid. The goal of this proposal is to assess whether genetically decreasing the catabolism of PtdIns(4,5)P2 in the brain of AD mouse models can ameliorate learning and memory deficits in various behavioral tasks.

描述（由申请人提供）：阿尔茨海默氏病（AD）是晚期痴呆症的最常见形式。越来越多的证据表明，淀粉样β肽（ABETA）的大脑升高和积累介导了疾病发病机理的许多方面。尽管AD患者的大脑通常包含由Abeta的不溶性骨料组成的淀粉样蛋白斑块，但在动物模型和AD的个体中，Abeta的可溶性寡聚形式的水平与认知能力下降和/或疾病进展更好。因此，最近已显示Abeta低聚物在海马中引起突触缺陷，至少部分通过调节谷氨酸受体通道的细胞表面水平，肌动蛋白动力学和钙稳态的能力。最近，我们研究了ABETA和磷脂酰肌醇-4,5-双磷酸[PTDINS（4,5）P2]之间的关系，这是一种关键的信号磷脂，该磷脂集中在控制多个过程的质膜上。我们发现，用可溶性ABETA低聚物的原代皮质神经元的治疗显着降低了PTDINS（4,5）P2水平，而对细胞生存能力没有明显影响。 PTDINS（4,5）P2下调是可逆的，需要细胞外Ca2+，并被谷氨酸（NMDA）受体拮抗剂所部分阻断。为了测试这种现象在Abeta突触破裂作用中的相关性，我们利用了一种小鼠遗传模型，其中导致突触中消除PTDINS（4,5）P2的主要途径是针对的。这些小鼠缺少一份synj1的副本，synj1是一种编码PTDINS（4,5）P2磷酸酶突触janin 1的基因。我们发现，在从Synj1 +/-小鼠中衍生的培养神经元中的Abeta低聚物未能下调PTDINS（4,5）P2。此外，Abeta对海马长期增强的抑制作用在Synj1 +/-小鼠的切片中受到了强烈抑制。总而言之，我们的发现提出了一个新的假设，即PTDINS（4,5）P2 Dyshomeostasis可能是Abeta在突触下的主要早期神经毒性作用的基础，而Synj1单倍耐药性可能允许保护这种肽的作用。尽管我们来自神经元培养物和切片制剂的生化和电生理学数据表明，PTDINS（4,5）P2在ABETA诱导的突触功能障碍中的核心作用（4,5），但一个基本问题是，这种现象是否与AD的病理生理学相关，特别是与这种障碍相关，因为该现象与这种疾病的病理生理学相关。为了开始解决这个问题并验证我们在体内的假设，我们计划测试Synj1单倍度不足是否赋予了AD动物模型中神经行为益处。 More specifically, we will generate double transgenic mice expressing familial AD-linked mutant versions of APP and presenilin 1 ("PSAPP mice") that are haploinsufficient for Synj1 and test whether these animals exhibit reduced age-dependent cognitive deficits relative to PSAPP mice using tests, such as fear conditioning, the radial-arm water maze and the Morris water maze.公共卫生相关性：阿尔茨海默氏病（AD）是晚期痴呆症的最常见形式。越来越多的证据表明，淀粉样β肽（ABETA）的大脑升高和积累介导了疾病发病机理的许多方面。最近，我们发现ABETA降低了磷脂酰肌醇-4,5-双磷酸[PTDINS（4,5）P2]，这是一种主要的生物活性细胞内脂质。该建议的目的是评估AD小鼠模型大脑中PTDINS（4,5）P2的分解代谢是否可以减轻各种行为任务中的学习和记忆缺陷。