Synaptic Plasticity In Aging And Neurodegenerative Disorders

衰老和神经退行性疾病中的突触可塑性

• 批准号: 7732200
• 负责人: MARK P MATTSON
• 金额: $ 90.62万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732200
• 关键词: Adrenal Glands; Adult; Affect; Aging; Alzheimer' s Disease; Animal Behavior; Animal Model; Antidepressive Agents; Apoptotic; Behavioral; Brain; Calcium; Caloric Restriction; Cell Surface Receptors; Chromosome Pairing; Chronic; Defect; Diabetes Mellitus; Disease; Elevation; Embryonic Development; Exhibits; Fasting; Functional disorder; Glucocorticoids; Hippocampus (Brain); Image; Impairment; Knockout Mice; Learning; Life; Ligands; Long-Term Potentiation; Memory; Memory impairment; Molecular; Molecular Abnormality; Mus; NF-kappa B; Neurodegenerative Disorders; Neurons; P2X-receptor; Paroxetine; Pharmaceutical Preparations; Physiologic pulse; Property; Proteins; Pulse taking; Rattus; Reporting; Role; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; TP53 gene; Technology; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Work; age related; amyloid pathology; dietary supplements; memory process; mouse model; nervous system development; neurogenesis; notch protein; novel; postsynaptic; research study; response; stem cell fate; synaptic function

The ability of synapses to change their properties in response to environmental demands (synaptic plasticity) is essential for learning and memory. Abnormalities in synaptic plasticity are involved in Alzheimers disease and related disorders. In our continuing efforts to understand the molecular mechanisms involved in synaptic plasticity, in the contexts of aging and neurodegenerative disorders, we have made two major advances. 1) During development of the nervous system, the fate of stem cells is regulated by a cell surface receptor called Notch. Notch is also present in the adult mammalian brain; however, because Notch null mice die during embryonic development, it has proven difficult to determine the functions of Notch. Here, we used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-kappa B activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes. 2) Although ATP is reported to modulate synaptic plasticity, the mechanism of action of ATP on synaptic transmission is not fully understood. Here we show that ATP enhances long-term potentiation (LTP), and P2X receptor antagonists inhibit this ATP effect, but do not affect paired pulse facilitation (PPF) in rat hippocampal slices. ATP rapidly increases intracellular calcium, and P2X receptor antagonists inhibit this increase in cultured dissociated neurons. These results indicate that ATP enhances LTP via activation of postsynaptic P2X receptors. In additional studies, we have found that intermittent fasting and caloric restriction ameliorate age-related learning and memory deficits in a novel transgenic mouse model of Alzheimers disease. We also found that the antidepressant drug paroxetine was effective in suppressing amyloid pathology and preserving learning and memory ability in the same mouse model of Alzheimers disease. Other experiments have shown that diabetes impairs hippocampal neurogenesis and synaptic plasticity as the result of a chronic elevation in the level of adrenal glucocorticoids. We are currently working on a project aimed at understanding the role of "apoptotic" proteins such as p53 in synaptic plasticity.

突触根据环境需求（突触可塑性）改变其性质的能力对于学习和记忆至关重要。 突触可塑性异常与阿尔茨海默氏病和相关疾病有关。 在我们继续努力理解突触可塑性所涉及的分子机制的过程中，在衰老和神经退行性疾病的背景下，我们取得了两个重大进步。 1）在神经系统的发展过程中，干细胞的命运受到称为Notch的细胞表面受体的调节。 Notch也存在于成年哺乳动物大脑中。但是，由于Notch Null小鼠在胚胎发育过程中死亡，因此很难确定Notch的功能。在这里，我们使用了正态开发和繁殖但表现出降低水平的Notch反义转基因小鼠，以证明缺口信号在突触可塑性中的作用。水位降低的小鼠在海马CA1突触上表现出长期增强（LTP）的受损。 Notch配体可以增强正常小鼠的LTP，并纠正Notch反义转基因小鼠LTP中的缺陷。在缺口水平降低的小鼠中，基底和刺激诱导的NF-kappa B活性显着降低。这些发现表明，Notch信号传导的重要作用以一种已知与学习和记忆过程相关的突触可塑性形式。 2）尽管据报道ATP调节突触可塑性，但ATP对突触传递的作用机理尚未完全了解。在这里，我们表明ATP增强了长期增强（LTP），而P2X受体拮抗剂抑制了这种ATP效应，但不会影响大鼠海马切片中的配对脉冲促进（PPF）。 ATP迅速增加细胞内钙，P2X受体拮抗剂抑制了培养的解离神经元的增加。这些结果表明，ATP通过突触后P2X受体的激活增强了LTP。 在其他研究中，我们发现，在阿尔茨海默氏病的新型转基因小鼠模型中，间歇性禁食和热量限制可以改善与年龄有关的学习和记忆缺陷。 我们还发现，抗抑郁药帕罗西汀在同一阿尔茨海默氏病小鼠模型中有效抑制淀粉样病理学并保持学习和记忆能力。 其他实验表明，由于肾上腺糖皮质激素水平的慢性升高，糖尿病会损害海马神经发生和突触可塑性。 我们目前正在研究一个旨在了解“凋亡”蛋白（例如p53）在突触可塑性中的作用的项目。

项目成果

Involvement of Fc receptors in disorders of the central nervous system.

• DOI: 10.1007/s12017-009-8099-5
• 发表时间: 2010-06
• 期刊: NEUROMOLECULAR MEDICINE
• 影响因子: 3.5
• 作者: Okun, Eitan;Mattson, Mark P.;Arumugam, Thiruma V.
• 通讯作者: Arumugam, Thiruma V.

Heterogeneity of endocytic proteins: distribution of clathrin adaptor proteins in neurons and glia.

内吞蛋白的异质性：网格蛋白接头蛋白在神经元和神经胶质细胞中的分布。

• DOI: 10.1016/s0306-4522(03)00431-7
• 发表时间: 2003
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Yao,PJ;Zhang,P;Mattson,MP;Furukawa,K
• 通讯作者: Furukawa,K

Dual effects of ATP on rat hippocampal synaptic plasticity.

ATP 对大鼠海马突触可塑性的双重影响。

• DOI: 10.1097/00001756-200403220-00012
• 发表时间: 2004
• 期刊: Neuroreport
• 影响因子: 1.7
• 作者: Wang,Yue;Haughey,NormanJ;Mattson,MarkP;Furukawa,Katsutoshi
• 通讯作者: Furukawa,Katsutoshi

Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity.

TNF 和 NF-κB 参与海马突触可塑性的证据。

• DOI: 10.1002/(sici)1098-2396(200002)35:2<151::aid-syn8>3.0.co;2-p
• 发表时间: 2000
• 期刊: Synapse (New York, N.Y.)
• 作者: Albensi,BC;Mattson,MP
• 通讯作者: Mattson,MP

Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease.

• DOI: 10.1016/j.neurobiolaging.2008.07.003
• 发表时间: 2010-06
• 期刊: NEUROBIOLOGY OF AGING
• 影响因子: 4.2
• 作者: Jo, Dong-Gyu;Arumugam, Thiruma V.;Woo, Ha-Na;Park, Jong-Sung;Tang, Sung-Chun;Mughal, Mohamed;Hyun, Dong-Hoon;Park, Jun-Hyung;Choi, Yun-Hyung;Gwon, A-Ryeong;Camandola, Simonetta;Cheng, Aiwu;Cai, Huaibin;Song, Weihong;Markesbery, William R.;Mattson, Mark P.
• 通讯作者: Mattson, Mark P.