The Abeta protein of Alzheimer's Disease is an antimicrobial peptide

描述（由申请人提供）：这项新的研究者申请详细介绍了确定阿尔茨海默病（AD）主要病理因子a¿正常功能的建议。A¿通常被描述为淀粉样蛋白前体蛋白（APP）的附带分解代谢副产物，没有功能作用。然而，a¿和典型的人类抗菌肽（AMP） LL-37的详细比较揭示了在物理化学和生物活性方面惊人的相似性。被认为是A¿异常病理行为的性质和作用介导LL-37的正常功能。我们认为A¿的生理化学和生物活性与先天免疫系统的抗菌肽的主要功能一致。与我们的假设一致，初步实验表明A¿抑制8种临床重要微生物的生长，包括白色念珠菌、大肠杆菌、表皮葡萄球菌、肺炎链球菌、金黄色葡萄球菌、单核增生李斯特菌、粪肠球菌和无乳链球菌。对于这些微生物中的至少两种，A¿是比LL-37更有效的抗菌剂。此外，实验还发现抗a¿免疫耗竭减弱的AD脑匀浆具有抗菌活性。从已知的A¿的物理化学推断，我们还确定了LL-37的新的金属介导的寡聚活性。寡聚化是AMP作用的关键步骤，初步实验表明a¿寡聚物具有增强的抗菌活性。与寡聚物在a¿s抗菌作用中的关键作用一致，我们的初步数据表明，肽与细菌细胞孵育也促进寡聚。不同的细菌种类被发现产生不同的A¿低聚物，包括高度神经毒性的sds稳定二聚体和三聚体。该研究将采用临床微生物学和分子生物学的既定方法来表征A¿的体外抗菌活性。此外，实验将研究寡聚物在抗菌作用中的作用，以及肽与微生物细胞的相互作用是否会产生具有高神经毒性的物种。在我们提出的研究的最后阶段，实验将测试APP敲除小鼠是否降低了对细菌性脑膜炎的抵抗力。相反，在中枢神经系统中过度表达A¿的转基因小鼠将被测试增加对细菌性脑膜炎的抵抗力。我们的项目是一个长期存在的，很大程度上被忽视的a¿生物学方面的新方法。我们认为这条调查路线很有可能产生真实而新颖的见解，这将有助于改善a¿的病理行为的更好策略。

DESCRIPTION (provided by applicant): This new investigator application details a proposal to identify the normal function of A¿, the leading pathological agent in Alzheimer's disease (AD). A¿ is most often characterized as an incidental catabolic byproduct of the amyloid precursor protein (APP) with no functional role. However, a detailed comparison of A¿ and the archetypical human antimicrobial peptide (AMP) LL-37 reveals striking similarities in physiochemical and biological activities. Properties and actions cited as abnormal pathological behavior for A¿ mediate normal functions of LL-37. We propose that the physiochemical and biological activities of A¿ are consistent with a primary function as an antimicrobial peptide of the innate immune system. Consistent with our hypothesis preliminary experiments show A¿ inhibits the growth of eight clinically important microorganisms, including Candida albicans, Escherichia coli, Staphylococcus epidermidis, Streptococcus pneumoniae, Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, and Streptococcus agalactiae. A¿ is a more potent antimicrobial agent than LL-37 for at least two of these microorganisms. Furthermore, experiments identified an antimicrobial activity in AD brain homogenates attenuated by anti-A¿ immunodepletion. Extrapolating from the known physiochemistry of A¿ we have also identified novel metal-mediated oligomerization activities for LL-37. Oligomerization is a key step in AMP action and preliminary experiments suggest A¿ oligomers have potentiated antimicrobial activity. Consistent with a key role for oligomers in A¿s antimicrobial action our preliminary data suggest incubation of the peptide with bacterial cells also promotes oligomerization. Different bacteria species were found to generate distinct A¿ oligomers, including highly neurotoxic SDS-stable dimers and trimers. The proposed study will use established methods from clinical microbiology and molecular biology to characterize the in vitro antimicrobial activity of A¿. In addition, experiments will investigate the role of oligomers in A¿s antimicrobial action and if interaction of the peptide with microbial cells generates species with high neurotoxicity. In the final phase of our proposed study experiments will test if APP knockout mice have reduced resistance to bacterial meningitis. Conversely, transgenic mice over-expressing A¿ in the CNS will be tested for increased resistance to bacterial meningitis. Our project is a fresh approach to a long standing and largely ignored aspect of A¿ biology. We feel this line of enquiry has a high probability of yielding real and novel insights that will facilitate better strategies for ameliorating the pathological actions of A¿. PUBLIC HEALTH RELEVANCE: The key inference of the proposed study is that the biomolecule most associated with AD pathology (A¿) normally functions as an antimicrobial agent and is a component of the innate immune system. If validated the identification of A¿ as an antimicrobial agent raises the possibility of preventing amyloidosis from starting by preemptive targeting of pathogens/insults that stimulate the brain's innate immune system. Secondly, it identifies the inflammatory pathways of the innate immune system as targets for modulating A¿ generation.