Mechanisms of Peroxiredoxin 6 Endowed Protection in Alzheimer’s Disease

过氧化还原蛋白 6 对阿尔茨海默病的保护机​​制

• 批准号: 10551833
• 负责人: MARTIN Joseph SADOWSKI
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551833
• 关键词: AD transgenic mice; APP-PS1; Abbreviations; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Animals; Applications Grants; Astrocytes; Attenuated; Behavioral; Brain; Breeding; Cell Lineage; Cognitive deficits; Containment; Data; Defense Mechanisms; Deposition; Diffuse; Disease; Dose; Endothelial Cells; Endothelium; Endowment; Enzymes; Epithelial Cells; Experimental Models; Genes; Impaired cognition; Individual; Inflammatory Response; Knock-in; Knock-out; Knockout Mice; Macrophage; Membrane Lipids; Microglia; Molecular; Mus; Mutant Strains Mice; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Outcome Measure; Pathway interactions; Penetration; Phagocytes; Phase; Phenotype; Phospholipase; Phospholipid Metabolism; Play; Point Mutation; Process; Proteins; Proteomics; Role; Senile Plaques; Severities; Signal Pathway; Signal Transduction; Site; Synapses; TREM2 gene; Testing; Therapeutic; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; Variant; Work; abeta accumulation; abeta deposition; alveolar epithelium; beta amyloid pathology; cell injury; genetic risk factor; glutathione peroxidase; mouse model; neuropathology; novel; overexpression; peroxiredoxin; pre-clinical; prevent; protective effect; proteostasis; receptor; repaired; response; transcriptomics

Project Summary β-amyloid (Aβ) deposition is the main culprit in preclinical phase of Alzheimer’s disease (AD). Its rate conditions severity of ensuing neurofibrillary degeneration and precipitates the onset of cognitive deficit. Identification of AD associated variants in the TREM2 receptor, which render microglia defective in processing Aβ plaques, well underscores the meaning of protective function glial cell play in Aβ proteostasis. Like microglia, astrocytes respond to Aβ deposits by altering their phenotype and function, yet molecular mechanisms governing astrocytic response and those underlying the cooperative cross-talk between astrocytes and microglia in countering Aβ deposition remain ill-defined. In this proposal, we put forward a novel hypothesis that an astrocytic protein Peroxiredoxin (PRDX) 6 plays a pivotal role in these two intertwined processes. PRDX6 has two independent enzymatic sites endowing glutathione peroxidase (Gpx) and phospholipase 2 (PLA2) activities. PRDX6 is abundantly expressed by alveolar epithelium and endothelial cells and it is responsible for repair of peroxidatively damaged cell membrane lipids, phospholipid metabolism, and cellular signaling. In the CNS, PRDX6 is expressed by astrocytes, and its role in neurodegeneration remains unexplored. Our hypothesis is based on extensive preliminary data showing that hemizygous knock in of the overexpressing Prdx6 transgene in APP/PS1 mouse model promotes selective enticement of astrocytes to Aβ plaques and penetration of plaques by astrocytic processes along with increased number and phagocytic activation of periplaque microglia. This effects suppression of nascent plaque seeding and remodeling of mature plaques consequently curtailing brain Aβ load and Aβ associated neuritic degeneration. Conversely, Prdx6 haplodeficiency attenuates astro- and microglia activation around Aβ plaques promoting Aβ deposition and neuritic degeneration. Thus, our data evidence that PRDX6 expression level in astrocytes circuitously modulates microglia function implying astrocyte-guided microglia effect in Aβ proteostasis. Furthermore, our showing that upregulation of PRDX6 attenuates Aβ pathology implies a novel disease modifying strategy for AD. Aim 1 of this application will use newly developed APP/PS1 mice, which are homozygous for the overexpressing Prdx6 transgene and APP/PS1 mice with Prdx6 knockout to determine the extent of Prdx6 overexpression expedience and conversely consequences of Prdx6 deletion on Aβ deposition, periplaque astro- and micro- glia response, Aβ-associated neurodegeneration and behavioral deficit. Aim 2 will dissect individual effects of Gpx and PLA2 functions on curtailing Aβ pathology through crossing APP/PS1 mice with readily available Prdx6 mutant mice, in which selective point mutations rendered either enzymatic site inactive. Aim 3 will employ transcriptomic approaches to identify molecular pathways involved in astro/microglia cross talk, which we expect to be altered by manipulating Prdx6 expression level in Prdx6 overexpressing and knockout mice. Transcriptomic approaches also will determine whether PRDX6 modulates activation phenotype of astrocytes and microglia and regulates glia inflammatory response.

项目摘要 β-淀粉样蛋白（Aβ）沉积是阿尔茨海默病（AD）临床前阶段的主要原因。其速率条件 严重程度的神经退行性变和沉淀的认知缺陷的发作。AD的识别 TREM 2受体的相关变体，使小胶质细胞在处理Aβ斑块时有缺陷， 强调了胶质细胞在Aβ蛋白稳定中发挥保护功能的意义。像小胶质细胞、星形胶质细胞一样 通过改变其表型和功能来响应Aβ沉积，但控制星形胶质细胞 反应和那些潜在的星形胶质细胞和小胶质细胞之间的合作串扰在对抗Aβ 沉积仍然不明确。在这个提议中，我们提出了一个新的假设， Peroxiredoxin（PRDX）6在这两个相互交织的过程中起着关键作用。PRDX 6有两个独立的 赋予谷胱甘肽过氧化物酶（Gpx）和磷脂酶2（PLA 2）活性的酶位点。PRDX 6是 在肺泡上皮细胞和内皮细胞中大量表达，负责过氧化损伤的修复， 受损的细胞膜脂质、磷脂代谢和细胞信号传导。在CNS中，PRDX 6是 它由星形胶质细胞表达，并且其在神经变性中的作用仍然未被探索。我们的假设是基于 大量的初步数据表明，在APP/PS1中过表达Prdx 6转基因的半合子敲入 小鼠模型促进星形胶质细胞对Aβ斑块的选择性诱导和星形胶质细胞对斑块的穿透 过程沿着斑块周围小胶质细胞的数量增加和吞噬激活。这实现 抑制新生斑块种植和成熟斑块重塑，从而减少脑Aβ负荷 和Aβ相关的神经炎变性。相反，Prdx 6单倍体缺陷减弱了星形胶质细胞和小胶质细胞的表达。 Aβ斑块周围的活化促进Aβ沉积和神经炎变性。因此，我们的数据证明， 星形胶质细胞中PRDX 6表达水平间接调节小胶质细胞功能，暗示星形胶质细胞引导的 小胶质细胞在Aβ蛋白稳定中的作用。此外，我们的研究表明，PRDX 6的上调可以减弱Aβ 病理学暗示了AD的新的疾病修饰策略。本应用程序的目标1将使用新开发的 过表达Prdx 6转基因纯合子的APP/PS1小鼠和具有Prdx 6的APP/PS1小鼠 敲除以确定Prdx 6过度表达的程度和Prdx 6过度表达的相反后果 缺失对Aβ沉积、斑块周围星形胶质细胞和小胶质细胞反应、Aβ相关神经变性和 行为缺陷目的2将剖析Gpx和PLA 2功能对减少Aβ病理的个体影响 通过将APP/PS1小鼠与容易获得的Prdx 6突变小鼠杂交， 使任一酶位点失活。目的3将采用转录组学方法来鉴定分子 参与星形/小胶质细胞串扰的途径，我们希望通过操纵Prdx 6表达来改变 在Prdx 6过表达和敲除小鼠中的水平。转录组学方法也将决定 PRDX 6调节星形胶质细胞和小胶质细胞的活化表型并调节胶质细胞炎症反应。