Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease

衰老和阿尔茨海默病中的钙调神经磷酸酶和炎症信号传导过程

• 批准号: 10531677
• 负责人: Christopher Mark Norris
• 金额: $ 24.93万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531677
• 关键词: Address; Administrative Supplement; Aging; Air; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animal Model; Area; Astrocytes; Autopsy; Blood - brain barrier anatomy; Blood Flow Velocity; Blood capillaries; Brain; Budgets; COVID-19 pandemic; Calcineurin; Caliber; Cells; Cephalic; Cerebrovascular Circulation; Cerebrovascular Disorders; Contralateral; Data; Dementia; Development; Diet; Dyes; Electrophysiology (science); Ensure; Equipment; Extravasation; Functional disorder; Funding; Glass; Glutamate Transporter; Glutamates; Hour; Human; Human Resources; Hyperactivity; Hyperhomocysteinemia; Image; Impaired cognition; Impairment; Inflammatory; Investigation; Kentucky; Knowledge; Lasers; Lead; Link; Maintenance; Methods; Microscope; Modeling; Molecular; Molecular Profiling; Mus; NFAT Pathway; Neurons; Optics; Parents; Pathologic; Pathology; Performance; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Procedures; Process; Reagent; Research; Research Personnel; Resources; Role; Running; Scanning; Schedule; Signal Transduction; Specimen; Synapses; System; Techniques; Testing; Time; Transgenic Animals; Universities; Vascular Cognitive Impairment; Vibrissae; Work; adeno-associated viral vector; arteriole; awake; barrel cortex; base; cell type; cerebrovascular; cerebrovascular pathology; comorbidity; coronavirus disease; druggable target; experimental study; imaging facilities; improved; innovation; insight; interdisciplinary approach; mixed dementia; molecular phenotype; mouse model; multidisciplinary; neurotoxic; neurovascular coupling; novel; patch clamp; post-COVID-19; rhodamine dextran; transcription factor; two photon microscopy; two-photon; uptake; vascular cognitive impairment and dementia; vector

Abstract (FROM ORIGINAL FUNDED PROPOSAL) Mounting evidence suggests that comorbid vascular contributions to cognitive impairment and dementia (VCID) may complicate the treatment of Alzheimer’s disease (AD)-related dementia. Our overarching hypothesis is that AD and VCID pathological sequelae converge at the level of activated astrocytes, providing a common druggable target for a wide range of dementias (i.e. AD alone, VCID alone, and mixed dementia). Central to this hypothesis is the Ca2+ -dependent phosphatase, calcineurin (CN), which appears at high levels in activated astrocytes and positively regulates multiple components of the activated astrocyte phenotype through direct interactions with NFAT transcription factors. We, and others have shown that hyperactivation of CN/NFAT occurs in astrocytes during early stages of cognitive decline in humans and mice with AD-like pathology and is linked to glutamate-dependent hyperexcitability. However, little is known about astrocytic CN/NFAT in VCID, presenting a critical knowledge gap in our understanding of mixed dementia. New preliminary data obtained from human cerebrovascular pathology cases and from an established diet-based VCID mouse model, suggest that hyperactive CN/NFAT signaling also arises with cerebrovascular pathology. Based on these observations, we predict that combined AD and VCID pathology will exacerbate aberrant CN/NFAT signaling leading to a “neurotoxic” astrocyte phenotype, characterized by the loss of EAAT2/Glt-1 glutamate transporters and impaired glutamate uptake. We further predict that normalization of the CN/NFAT/Glt-1 axis, using cell-type specific AAV vectors and novel pharmacologic agents, will alleviate neuronal and cerebrovascular abnormalities in AD, VCID, and mixed AD/VCID models. Our overarching hypothesis and corollary predictions will be tested using human biospecimens and relevant mouse models including the hyperhomocysteinemia (HHcy) model of VCID and the 5xFAD model of A pathology. Aim 1 will test the hypothesis that mixed AD and VCID pathologies in both humans and mice converge to exacerbate CN/NFAT hyperactivity in astrocytes, leading to a neurotoxic astrocyte molecular phenotype. Aim 2 will test the hypothesis that the astrocytic CN/NFAT/Glt-1 axis drives cerebrovascular dysfunction in AD, VCID, and mixed VCID/AD models. And Aim 3 will test the hypothesis that the astrocytic CN/NFAT/Glt-1 axis drives hyperexcitability, synapse dysfunction, and cognitive loss in AD, VCID, and mixed VCID/AD models. These aims will be pursued using novel reagents, and cutting-edge multidisciplinary approaches. This work is essential for assessing the role of astrocytic CN/NFATs in VCID and mixed pathology and may help stimulate the development of astrocyte- targeted approaches for treating a broad range of dementia cases.

摘要（来自原始资助提案） 越来越多的证据表明，共病血管导致认知障碍和 痴呆症 (VCID) 可能会使阿尔茨海默病 (AD) 相关痴呆症的治疗变得复杂。 总体假设是 AD 和 VCID 病理后遗症集中在激活的水平上 星形胶质细胞，为多种痴呆症（即单独的 AD、单独的 VCID、 该假说的核心是 Ca2+ 依赖性磷酸酶，即钙调神经磷酸酶 (CN)。 在活化的星形胶质细胞中出现高水平，并积极调节星形胶质细胞的多种成分 We 等人通过与 NFAT 转录因子直接相互作用激活星形胶质细胞表型。 研究表明，在认知能力下降的早期阶段，星形胶质细胞中 CN/NFAT 过度激活 在患有 AD 样病理的人类和小鼠中，这种现象与谷氨酸依赖性过度兴奋有关。 然而，人们对 VCID 中的星形胶质细胞 CN/NFAT 知之甚少，这在我们的研究中呈现出关键的知识差距。 对混合性痴呆的认识。 从人类脑血管病理病例和已建立的研究中获得的新初步数据 基于饮食的 VCID 小鼠模型表明，脑血管疾病也会出现过度活跃的 CN/NFAT 信号传导 基于这些观察，我们预测 AD 和 VCID 病理学相结合。 加剧的异常 CN/NFAT 信号传导导致“神经毒性”星形胶质细胞表型，其特征是 我们进一步预测，EAAT2/Glt-1 谷氨酸转运蛋白的丢失和谷氨酸吸收受损。 使用细胞类型特异性 AAV 载体和新型药理学使 CN/NFAT/Glt-1 轴正常化 药物，将减轻 AD、VCID 和混合 AD/VCID 的神经元和脑血管异常 我们的总体假设和推论预测将使用人类生物样本进行测试。 以及相关的小鼠模型，包括VCID的高同型半胱氨酸血症（HHcy）模型和5xFAD A 病理学模型的目标 1 将检验人类中 AD 和 VCID 病理学混合的假设。 小鼠聚集会加剧星形胶质细胞中的 CN/NFAT 过度活跃，导致神经毒性星形胶质细胞 目标 2 将检验星形胶质细胞 CN/NFAT/Glt-1 轴驱动的假设。 AD、VCID 和混合 VCID/AD 模型中的脑血管功能障碍将进行测试。 假设星形胶质细胞 CN/NFAT/Glt-1 轴驱动过度兴奋、突触功能障碍和 AD、VCID 和混合 VCID/AD 模型中的认知损失将使用新颖的方法来实现。 这项工作对于评估其作用至关重要。 星形胶质细胞 CN/NFAT 在 VCID 和混合病理学中的作用，可能有助于刺激星形胶质细胞的发育 治疗各种痴呆症病例的有针对性的方法。

项目成果

Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model.

在 CAMKII-tTa 转基因小鼠模型中，人 wtTDP-43 的过度表达会导致海马可塑性受损和行为缺陷。

• 发表时间: 2020
• 作者: Quadri, Zainuddin;Johnson, Nicholas;Zamudio, Frank;Miller, Abraian;Peters, Melinda;Smeltzer, Shayna;Hunt Jr, Jerry B;Housley, Steven B;Brown, Breanna;Kraner, Susan;Norris, Christopher M;Nash, Kevin;Weeber, Edwin;Lee, Daniel C;Selenica, Maj
• 通讯作者: Selenica, Maj

In Vivo Single-Molecule Detection of Nanoparticles for Multiphoton Fluorescence Correlation Spectroscopy to Quantify Cerebral Blood Flow.

用于多光子荧光相关光谱的纳米粒子的体内单分子检测以量化脑血流量。

• 发表时间: 2020
• 影响因子: 10.8
• 作者: Fu, Xu;Sompol, Pradoldej;Brandon, Jason A;Norris, Christopher M;Wilkop, Thomas;Johnson, Lance A;Richards, Christopher I
• 通讯作者: Richards, Christopher I

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice.

激活的星形胶质细胞中的钙调神经磷酸酶/NFAT 信号驱动 Aβ 小鼠的网络过度兴奋。

• 发表时间: 2017
• 作者: Sompol, Pradoldej;Furman, Jennifer L;Pleiss, Melanie M;Kraner, Susan D;Artiushin, Irina A;Batten, Seth R;Quintero, Jorge E;Simmerman, Linda A;Beckett, Tina L;Lovell, Mark A;Murphy, M Paul;Gerhardt, Greg A;Norris, Christopher M
• 通讯作者: Norris, Christopher M

Calcineurin: directing the damage in Alzheimer disease: An Editorial for 'Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain' on page 24.

钙调神经磷酸酶：指导阿尔茨海默病的损害：第 24 页“神经钙调神经磷酸酶转录目标与阿尔茨海默病大脑中观察到的平行变化”的社论。

• 发表时间: 2018
• 影响因子: 4.7
• 作者: Norris; Christopher M
• 通讯作者: Christopher M

Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury.

阻断星形细胞钙调神经磷酸酶/NFAT 信号传导有助于使创伤性脑损伤大鼠模型的海马突触功能和可塑性正常化。

• 发表时间: 2016-02-03
• 作者: Furman, Jennifer L;Sompol, Pradoldej;Kraner, Susan D;Pleiss, Melanie M;Putman, Esther J;Dunkerson, Jacob;Mohmmad Abdul, Hafiz;Roberts, Kelly N;Scheff, Stephen W;Norris, Christopher M
• 通讯作者: Norris, Christopher M