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: 9975324
• 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/9975324
• 关键词: AD transgenic mice; APP-PS1; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Animals; Applications Grants; Astrocytes; Attenuated; Behavioral; Brain; Cell Lineage; Cognitive deficits; Containment; Data; Defense Mechanisms; Deposition; Diffuse; Disease; Dose; Endothelial Cells; Endothelium; Enzymes; Epithelial Cells; Experimental Models; Genes; Impaired cognition; Individual; Inflammatory Response; Knock-in; Knock-out; Knockout Mice; Membrane Lipids; Microglia; Molecular; Mus; Mutant Strains Mice; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Outcome Measure; Pathology; Pathway interactions; Penetration; Peptides; Peroxides; Phagocytes; Phase; Phenotype; Phospholipase; Phospholipase A2; Phospholipid Metabolism; Play; Point Mutation; Process; Proteins; Proteomics; Role; Senile Plaques; Severities; Signal Pathway; Signal Transduction; Site; Synapses; Testing; Therapeutic; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; Variant; Work; abeta accumulation; abeta deposition; alveolar epithelium; base; cell injury; genetic risk factor; glutathione peroxidase; macrophage; mouse model; 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 淀粉样蛋白(β-β，A-A)沉积是阿尔茨海默病(AD)临床前期的主要原因。它的费率条件 严重的神经原纤维变性，并加速认知功能障碍的发生。AD的识别 TREM2受体中的相关变异使小胶质细胞在处理Aβ斑块时出现缺陷， 强调了神经胶质细胞在Aβ蛋白平衡中的保护功能的意义。像小胶质细胞一样，星形胶质细胞 通过改变Aβ沉积的表型和功能来响应其沉积，但调控星形细胞的分子机制 星形胶质细胞和小胶质细胞在对抗β中的反应及其潜在的协同串扰 证词仍然定义不清。在这个提议中，我们提出了一个新的假设，即一种星形细胞蛋白 过氧化还蛋白(PRDX)6在这两个相互交织的过程中起着关键作用。PRDX6有两个独立的 具有谷胱甘肽过氧化物酶(GPX)和磷脂酶2(PLA2)活性的酶部位。PRDX6是 肺泡上皮和内皮细胞大量表达，参与过氧化损伤的修复 破坏细胞膜脂质、磷脂代谢和细胞信号。在CNS中，PRDX6是 由星形胶质细胞表达，其在神经退行性变中的作用尚不清楚。我们的假设是基于 大量的初步数据表明，APP/PS1中过表达的Prdx6转基因的半合子敲入 小鼠模型促进星形胶质细胞对Aβ斑块的选择性引诱和星形胶质细胞对斑块的穿透 随着斑块周围小胶质细胞数量的增加和吞噬活性的增加而发生的过程。这会影响 抑制新生斑块种植和成熟斑块重塑从而降低脑Aβ负荷 和β相关性神经元性变性。相反，Prdx6单倍体缺陷会削弱星形胶质细胞和小胶质细胞 Aβ斑块周围的激活促进Aβ沉积和神经细胞变性。因此，我们的数据证明 星形胶质细胞PRDX6表达水平迂回调节小胶质细胞功能暗示星形胶质细胞引导 小胶质细胞在β蛋白平衡中的作用。此外，我们的研究表明，PrDX6的上调可以减弱Aβ 病理学为AD提供了一种新的疾病改善策略。此应用程序的目标1将使用新开发的 过表达Prdx6基因纯合子的APP/PS1小鼠和携带Prdx6基因的APP/PS1小鼠 基因敲除以确定Prdx6过度表达的便利程度以及Prdx6的反之后果 Aβ沉积缺失、斑块周围星形胶质细胞和小胶质细胞反应、β相关性神经变性和 行为缺陷。目标2将剖析GPx和PLA2功能在抑制Aβ病理中的单独作用 通过将APP/PS1小鼠与现成的Prdx6突变小鼠杂交，其中选择性点突变 使两种酶的任何一种都不活跃。目标3将使用转录转录方法来鉴定分子 参与天文/小胶质细胞串扰的通路，我们希望通过操纵Prdx6的表达来改变 在Prdx6过表达和基因敲除小鼠中的水平。转录切割方法也将决定 PRDX6调节星形胶质细胞和小胶质细胞的激活表型，调节神经胶质细胞的炎症反应。