Presenilin 2 and Neuroinflammation

早老素 2 和神经炎症

• 批准号: 8865696
• 负责人: SUMAN JAYADEV
• 金额: $ 34.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8865696
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Autopsy; Behavior; Brain; Cause of Death; Cell Culture Techniques; Cell Line; Cells; Characteristics; Cleaved cell; Complex; Dementia; Development; Effector Cell; Functional disorder; Gene Expression; Genes; Goals; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lead; MicroRNAs; Microglia; Modeling; Molecular; Mutation; Natural Immunity; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Nonsense Codon; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Presenile Alzheimer Dementia; Production; Proteins; Regulation; Role; Signaling Molecule; System; Therapeutic Intervention; Tissues; Toll-Like Receptor Pathway; Transgenic Animals; Transgenic Mice; United States; Up-Regulation; cell type; cytokine; familial Alzheimer disease; human IRAK1 protein; in vivo; inhibitor/antagonist; insight; macrophage; mind control; mouse model; mutant; mutation carrier; neuroinflammation; neuropathology; novel; presenilin; presenilin-1; presenilin-2; research study; secretase; small hairpin RNA; targeted treatment; therapeutic target; therapy design; white matter

DESCRIPTION (provided by applicant): Alzheimer disease is the leading cause of dementia and the 6th commonest cause of death in the United States. Familial Alzheimer disease (fAD) is associated with mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). PS1 and PS2 are the enzymatic component of the γ-secretase complex that cleaves APP to release the Aß42 peptide. Despite more that 15 years of study, a clear understanding of how mutations in PS1 and PS2 cause PS dysfunction and subsequent neurodegeneration has not emerged. The "amyloid hypothesis" suggests that Alzheimer disease (AD) develops as a toxic gain of presenilin function leading to excessive production of Aß42. However, therapeutic interventions directed at decreasing ß42 in AD have not yet yielded clinically practical treatments. It is becoming clear that additional mechanisms including neuroinflammation contribute to the development or progression of AD and thus may be additional potential avenues for therapy design. While AD associated PS mutations can lead to a higher Aß42:40 ratio in vitro, many concomitantly lead to impaired γ-secretase cleavage of substrates with well described roles in inflammation, development and differentiation. Therefore, PS mutations may have damaging consequences to basic cellular pathways. We have recently described an early onset AD patient who carries a novel PS2 premature termination codon mutation leading to decreased PS2 protein, supporting the hypothesis that loss of PS2 function can contribute to neurodegeneration. Conditional PS1/PS2 knockout mice recapitulate many features of AD including neurodegeneration, upregulation of inflammatory genes, and increased numbers of microglia, the primary innate immune effector cells in the CNS. We found in both PS2 shRNA stably expressing microglia cell lines and primary microglia isolated from PS2 knockout mice that PS2 deficiency is associated with an exaggerated release of pro- inflammatory cytokines. These results were reproducible in microglia exposed to a pharmacological γ-secretase inhibitor suggesting that PS2 modulates microglia through its enzymatic activity. We have also determined that one possible mechanism by which PS2 impacts microglia behavior is through regulation of two innate immunity associated microRNAs, miR146a and miR146b. PS2 deficiency is associated with decreased levels of miR146a/b and increased levels of the miR146a target, the inflammatory signaling molecule, IRAK-1. Taken together, these observations support the hypothesis that decreased PS2 function may contribute to neurodegeneration in AD by enhancing microglial neuroinflammation. In this proposal we will 1) evaluate the central nervous system inflammatory profile of patients with PS2 mutation associated familial and sporadic AD 2) investigate the regulation of miR146a/b by PS2 and 3) study the neuroinflammatory characteristics of a transgenic mouse model conditionally expressing the most common PS2 fAD associated mutation.

描述(由申请人提供)：阿尔茨海默病是美国痴呆症的主要原因，也是第六大最常见的死亡原因。家族性阿尔茨海默病(FAD)与编码淀粉样前体蛋白(APP)、早老素1(PS1)和早老素2(PS2)的基因突变有关。PS1和PS2是γ-分泌酶复合体的酶组分，它裂解APP释放A？42肽。尽管经过了15年多的研究，但对PS1和PS2突变是如何导致PS功能障碍和随后的神经退化的清楚了解尚未出现。“淀粉样蛋白假说”认为，阿尔茨海默病(AD)的发展是由于早老素功能的毒性获得，导致A？42的过量产生。然而，针对AD患者的治疗干预措施还没有产生临床实用的治疗方法。越来越清楚的是，包括神经炎症在内的其他机制有助于AD的发展或进展，因此可能是治疗设计的额外潜在途径。虽然与AD相关的PS突变可以在体外导致更高的A？42：40比率，但许多突变同时会导致底物的γ分泌酶裂解受损，这些底物在炎症、发育和分化中的作用已被熟知。因此，PS突变可能会对基本的细胞通路造成破坏性后果。我们最近描述了一例早发性AD患者，他携带一种新的PS2提前终止密码子突变，导致PS2蛋白减少，支持PS2功能丧失可导致神经退行性变的假设。条件性PS1/PS2基因敲除小鼠概括了AD的许多特征，包括神经变性、炎症基因上调和小胶质细胞的数量增加，小胶质细胞是中枢神经系统中主要的先天免疫效应细胞。我们发现，在稳定表达PS2 shRNA的小胶质细胞系和从PS2基因敲除小鼠分离的原代小胶质细胞中，PS2缺乏与促炎细胞因子的过度释放有关。这些结果在暴露于药物γ分泌酶抑制剂的小胶质细胞中是可以重现的，这表明PS2通过其酶活性调节小胶质细胞。我们还确定了PS2影响小胶质细胞行为的一个可能机制是通过调节两个与先天免疫相关的microRNAs，miR146a和miR146b。PS2缺乏与miR146a/b水平降低和miR146a靶标、炎症信号分子IRAK-1水平升高有关。综上所述，这些观察结果支持这一假说，即PS2功能降低可能通过增强小胶质细胞神经炎症而导致AD的神经退行性变。在这项建议中，我们将1)评估PS2突变相关的家族性和散发性AD患者的中枢神经系统炎症情况；2)研究PS2对miR146a/b的调节；3)研究有条件地表达最常见的PS2 FAD相关突变的转基因小鼠模型的神经炎症特征。