Peroxynitrite is a Molecular Determinant of Impaired Microvascular Energetics in Alzheimer's Disease

过氧亚硝酸盐是阿尔茨海默氏病微血管能量受损的分子决定因素

• 批准号: 10631129
• 负责人: Prasad V Katakam
• 金额: $ 63.39万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631129
• 关键词: Acceleration; Age; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Antioxidants; Behavioral; Biochemical; Bioenergetics; Biological Assay; Blood Vessels; Brain; C57BL/6 Mouse; Cells; Citric Acid Cycle; Dependence; Diabetes Mellitus; Discrimination; Electron Spin Resonance Spectroscopy; Estrogens; Female; Free Radicals; Genus Hippocampus; Glycolysis; Hormones; Human; Impaired cognition; Impairment; Insulin; Knock-in; Measures; Mediating; Metabolic; Methods; Microscopy; Microvascular Dysfunction; Mitochondria; Molecular; Mus; Neurodegenerative Disorders; Nitric Oxide; Obesity; Oxidative Phosphorylation; Perceptual learning; Peroxonitrite; Physiological; Pilot Projects; Play; Porphyrins; Production; Protons; Reactive Oxygen Species; Reporting; Research; Respiration; Respiratory physiology; Risk; Role; Severities; Sex Differences; Signal Transduction; Stress; Technology; Testing; Texture; Vibrissae; age related; aged; awake; cerebral microvasculature; cerebrovascular; cognitive function; comparison control; enzyme activity; extracellular; high throughput screening; in vivo; ischemic injury; male; molecular targeted therapies; mouse model; neglect; neurovascular coupling; neurovascular unit; novel; protein expression; response; senescence; sensor; sex; therapeutic target; two photon microscopy; two-photon

Summary Brain microvessels (BMVs) play an important role in the neurovascular coupling (NVC). Mitochondria are energy sensors of cells and impaired mitochondrial respiratory function initiate critical signaling detrimental to NVC leading to impaired cognitive function associated with Alzheimer's disease (AD). Our recent technological breakthrough utilizing Agilent Seahorse XFe extracellular flux analyzer developed a mitochondrial respiration assay in BMVs. Using this novel method, we observed age-dependent impairment of mitochondrial respiration and bioenergetics in BMVs from male and female C57Bl/6 mice. Notably, we found that BMVs from APP NL-G-F Knock-in model of AD display impaired mitochondrial respiration and accelerated senescence. Furthermore, we observed that young and aged female mice display sex-dependent differences in microvascular energetics related to the relative contribution of oxidative phosphorylation and glycolysis to overall energy production. Finally, we found that peroxynitrite scavenger (FeTMPyP) treatment enhanced non-mitochondrial respiration young female mice but enhanced proton leak in young male mice indicating that the differential peroxynitrite activity is sex-dependent. Therefore, we hypothesize that peroxynitrite differentially regulates microvascular mitochondrial function sex-dependently and is the molecular determinant of exaggerated age-related impairment of NVC and cognitive function in AD. We will employ male and female AD and C57Bl/6 mice of 8 months and 20 months age. Aim 1 will determine the sex dependent differential impact of peroxynitrite on the bioenergetics and enzyme activities (Krebs cycle, glycolysis, and antioxidants) in BMVs ex vivo. Aim 2 will determine the sex dependent differential impact of peroxynitrite on in vivo NVC responses to whisker deflections by two-photon excitation microscopy in awake mice. Aim 3 will determine the sex dependent differential impact of FeTMPyP on cognitive function by assessing whisker-dependent perceptual learning using the novel texture discrimination task. The results of this proposal would challenge the existing dogma and will demonstrate the sex-specific physiological role of peroxynitrite in regulating the microvascular bioenergetics and neurovascular unit. Furthermore, our results will firmly establish microvascular peroxynitrite as a potential therapeutic target in sex- dependent vulnerability and severity of AD and other neurodegenerative diseases.

概括 脑微血管（BMV）在神经血管耦合（NVC）中发挥着重要作用。线粒体是能量 细胞传感器和线粒体呼吸功能受损会启动对 NVC 有害的关键信号传导 导致与阿尔茨海默病（AD）相关的认知功能受损。我们最近的技术 利用安捷伦 Seahorse XFe 细胞外通量分析仪实现线粒体呼吸的突破 BMV 中的测定。使用这种新方法，我们观察到线粒体呼吸的年龄依赖性损伤 以及雄性和雌性 C57Bl/6 小鼠 BMV 的生物能学。值得注意的是，我们发现来自 APP NL-G-F 的 BMV AD 敲入模型显示线粒体呼吸受损并加速衰老。此外，我们 观察到年轻和老年雌性小鼠的微血管能量表现出性别依赖性差异 与氧化磷酸化和糖酵解对总体能量产生的相对贡献有关。 最后，我们发现过氧亚硝酸盐清除剂（FeTMPyP）处理增强了非线粒体呼吸 年轻雌性小鼠但年轻雄性小鼠的质子泄漏增加，表明差异过氧亚硝酸盐 活动具有性别依赖性。因此，我们假设过氧亚硝酸盐差异调节微血管 线粒体功能具有性别依赖性，是过度年龄相关损伤的分子决定因素 AD 中的 NVC 和认知功能。我们将使用 8 个月和 20 只雄性和雌性 AD 和 C57Bl/6 小鼠 月龄。目标 1 将确定过氧亚硝酸盐对生物能学和性别依赖性的差异影响 BMV 离体酶活性（克雷布斯循环、糖酵解和抗氧化剂）。目标2将决定性别 过氧亚硝酸盐对体内 NVC 对双光子晶须偏转响应的差异影响 清醒小鼠的激发显微镜检查。目标 3 将确定 FeTMPyP 对性别的差异影响 通过使用新颖的纹理辨别来评估依赖于胡须的感知学习的认知功能 任务。该提案的结果将挑战现有的教条，并将证明性别特异性 过氧亚硝酸盐在调节微血管生物能和神经血管单位中的生理作用。 此外，我们的结果将坚定地确立微血管过氧亚硝酸盐作为性行为的潜在治疗靶点。 AD 和其他神经退行性疾病的脆弱性和严重性相关。

项目成果

Amyloid [Formula: see text] (1-42) peptide impairs mitochondrial respiration in primary human brain microvascular endothelial cells: impact of dysglycemia and pre-senescence.

• DOI: 10.1007/s11357-022-00644-x
• 发表时间: 2022-08
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: Siva S. V. P. Sakamuri;V. Sure;Xiaoying Wang;G. Bix;V. Fonseca;R. Mostany;P. Katakam

Sex-dependent Regulation of Mitochondrial Respiratory Function in Mouse Brain Microvessels by Peroxynitrite Decomposition Catalyst.

过氧亚硝酸盐分解催化剂对小鼠脑微血管线粒体呼吸功能的性别依赖性调节。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Sakamuri,SivaS;Sure,VenkataN;Kolli,Lahari;Wisen,WilliamP;Evans,WesleyR;Lindsey,SarahH;Mostany,Ricardo;Katakam,PrasadV
• 通讯作者: Katakam,PrasadV

Fibrinogen in mice cerebral microvessels induces blood-brain barrier dysregulation with aging via a dynamin-related protein 1-dependent pathway.

• DOI: 10.1007/s11357-023-00988-y
• 发表时间: 2024-02
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Chandra, Partha K.;Selvam, Manesh Kumar Panner;Castorena-Gonzalez, Jorge A.;Rutkai, Ibolya;Sikka, Suresh C.;Mostany, Ricardo;Busija, David W.
• 通讯作者: Busija, David W.

Nitric oxide synthase inhibitor is an effective therapy for ischemia-reperfusion injury in mice.

一氧化氮合酶抑制剂是治疗小鼠缺血再灌注损伤的有效方法。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Wisen,WilliamP;Evans,WesleyR;Sure,VenkataN;Sperling,JaredA;Sakamuri,SivaS;Mostany,Ricardo;Katakam,PrasadV
• 通讯作者: Katakam,PrasadV