Identification and characterization of Aβ peptide interactors in Alzheimer's disease by structural approaches.
Identification and characterization of Aβ peptide interactors in Alzheimer's disease by structural approaches.
复制标题
DOI：
10.3389/fnagi.2014.00265
复制
发表时间：
2014
影响因子：
4.8
通讯作者：
Glucksman MJ
中科院分区：
文献类型：
--
作者：
Philibert KD;Marr RA;Norstrom EM;Glucksman MJ
目前，有非常有限的药物干预阿尔茨海默氏病（AD），以减轻淀粉样蛋白的负担牵连的疾病的病理生理。阿尔茨海默病的免疫组织学特征是大脑中老年斑的积累，患者逐渐丧失短期记忆，最终丧失认知能力。虽然AD患者的临床诊断和护理已经取得了显着改善，但这种毁灭性疾病的有效治疗仍然难以捉摸。AD的淀粉样蛋白负荷的关键组分来自淀粉样蛋白-β（Aβ）肽的积累，其来自被称为分泌酶的酶对淀粉样蛋白前体蛋白（APP）的加工，导致产生这些40-42个氨基酸的毒性Aβ肽。在最合理的抑制分泌酶活性的途径在改善AD进展方面似乎不是最佳的之后，减少Aβ的新治疗方法是必要的。新的治疗方法可以从蛋白质组学生物标志物倡议中收集，以产生酶及其潜在底物的详细分子相互作用。通过破译细胞中形成的蛋白质复合物来解释APPome是一种互补的方法，可以揭示与淀粉样蛋白生成肽前体的新型分子相互作用，以了解生物学并开发潜在的上游药物靶标。利用这些策略，我们已经鉴定了EC 3.4.24.15（EP24.15），一种与脑啡肽酶（NEP）相关的锌金属蛋白酶，通过首先检查计算机模拟对接的可能性，然后通过质谱法进行验证，具有分解代谢Aβ 1-42的能力。此外，还鉴定了一种激素载体蛋白甲状腺素运载蛋白（TTR），由于其在脑脊液（CSF）中的丰度，发现其可通过抑制Aβ肽寡聚体的形成来清除Aβ。互补策略的汇合可能允许新的治疗途径以及AD的生物标志物，这将有助于诊断，预后和治疗。
Currently, there are very limited pharmaceutical interventions for Alzheimer’s disease (AD) to alleviate the amyloid burden implicated in the pathophysiology of the disease. Alzheimer’s disease is characterized immunohistologically by the accumulation of senile plaques in the brain with afflicted patients progressively losing short-term memory and, ultimately, cognition. Although significant improvements in clinical diagnosis and care for AD patients have been made, effective treatments for this devastating disease remain elusive. A key component of the amyloid burden of AD comes from accumulation of the amyloid-beta (Aβ) peptide which comes from processing of the amyloid precursor protein (APP) by enzymes termed secretases, leading to production of these toxic Aβ peptides of 40–42 amino acids. New therapeutic approaches for reducing Aβ are warranted after the most logical avenues of inhibiting secretase activity appear less than optimal in ameliorating the progression of AD.Novel therapeutics may be gleaned from proteomics biomarker initiatives to yield detailed molecular interactions of enzymes and their potential substrates. Explicating the APPome by deciphering protein complexes forming in cells is a complementary approach to unveil novel molecular interactions with the amyloidogenic peptide precursor to both understand the biology and develop potential upstream drug targets. Utilizing these strategies we have identified EC 3.4.24.15 (EP24.15), a zinc metalloprotease related to neprilysin (NEP), with the ability to catabolize Aβ 1–42 by examining first potential in silico docking and then verification by mass spectrometry. In addition, a hormone carrier protein, transthyreitin (TTR), was identified and with its abundance in cerebrospinal fluid (CSF), found to clear Aβ by inhibiting formation of oligomeric forms of Aβ peptide. The confluence of complementary strategies may allow new therapeutic avenues as well as biomarkers for AD that will aid in diagnosis, prognosis and treatment.