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（来自原始资助的提案） 越来越多的证据表明，合并的血管对认知障碍和 痴呆症（VCID）可能会使阿尔茨海默氏病（AD）相关痴呆的治疗复杂化。我们的 总体假设是AD和VCID病理后遗症在激活的水平上收敛 星形胶质细胞为广泛的痴呆症提供了一个常见的可药物靶标（即单独进行广告，单独使用VCID， 和混合痴呆症）。该假设的核心是Ca2+依赖性磷酸酶钙调神经酶（CN），该磷酸酶，它 在活化的星形胶质细胞中出现高水平，并积极调节 通过与NFAT转录因子直接相互作用，激活的星形胶质细胞表型。我们和其他人 已经表明，在认知能力下降的早期，CN/NFAT的过度激活发生在星形胶质细胞中 在具有AD样病理学的人和小鼠中，与谷氨酸依赖性过度兴奋性有关。 但是，关于VCID中星形胶质细胞CN/NFAT知之甚少，在我们的 理解混合痴呆症。 从人类脑血管病理病例获得的新初步数据以及已建立的 基于饮食的VCID小鼠模型，表明脑血管发动过度活跃的CN/NFAT信号传导 病理。基于这些观察结果，我们预测合并的AD和VCID病理将 恶化的异常CN/NFAT信号传导导致“神经毒性”的星形胶质细胞表型，其特征是 EAAT2/GLT-1谷氨酸转运蛋白和谷氨酸摄取的损失。我们进一步预测 CN/NFAT/GLT-1轴的归一化，使用细胞类型的特异性AAV载体和新型药理学 代理会减轻AD，VCID和混合AD/VCID的神经元和脑血管异常 型号。我们的总体假设和推论预测将使用人类生物测量进行测试 和相关的小鼠模型，包括VCID和5XFAD的高脑膜半胱氨酸血症（HHCY）模型 A病理的模型。 AIM 1将测试两个人中混合AD和VCID病理的假设 小鼠会收敛于星形胶质细胞中的CN/NFAT多动症，导致神经毒性星形胶质细胞 分子表型。 AIM 2将检验星形细胞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。 AIM 3将测试 假设星形胶质细胞CN/NFAT/GLT-1轴可驱动过度刺激性，突触功能障碍和 AD，VCID和混合VCID/AD模型的认知损失。这些目标将使用小说追求 试剂和尖端的多学科方法。这项工作对于评估角色至关重要 VCID和混合病理中的星形细胞CN/NFAT，可能有助于刺激星形胶质细胞的发展 有针对性的方法来治疗广泛的痴呆病例。

项目成果

Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer's disease.

• DOI: 10.1016/j.arr.2021.101335
• 发表时间: 2021-07
• 期刊: Ageing research reviews
• 影响因子: 13.1
• 作者: Price BR;Johnson LA;Norris CM
• 通讯作者: Norris CM

Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats.

• DOI: 10.1371/journal.pone.0038170
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sama DM;Mohmmad Abdul H;Furman JL;Artiushin IA;Szymkowski DE;Scheff SW;Norris CM
• 通讯作者: Norris CM

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

• DOI: 10.1021/acs.nanolett.0c02280
• 发表时间: 2020-08-12
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Fu X;Sompol P;Brandon JA;Norris CM;Wilkop T;Johnson LA;Richards CI
• 通讯作者: Richards CI

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。

• DOI: 10.1111/jnc.14475
• 发表时间: 2018
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Norris,ChristopherM

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

• DOI: 10.1016/j.mcn.2019.103418
• 发表时间: 2020-01
• 期刊: Molecular and cellular neurosciences
• 作者: Quadri Z;Johnson N;Zamudio F;Miller A;Peters M;Smeltzer S;Hunt JB Jr;Housley SB;Brown B;Kraner S;Norris CM;Nash K;Weeber E;Lee DC;Selenica MB
• 通讯作者: Selenica MB