Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, United States of America.
PLoS One. 2010 Nov 3;5(11):e13820. doi: 10.1371/journal.pone.0013820.
Lactic acid, a natural by-product of glycolysis, is produced at excess levels in response to impaired mitochondrial function, high-energy demand, and low oxygen availability. The enzyme involved in the production of β-amyloid peptide (Aβ) of Alzheimer's disease, BACE1, functions optimally at lower pH, which led us to investigate a potential role of lactic acid in the processing of amyloid precursor protein (APP).
METHODOLOGY/PRINCIPAL FINDINGS: Lactic acid increased levels of Aβ40 and 42, as measured by ELISA, in culture medium of human neuroblastoma cells (SH-SY5Y), whereas it decreased APP metabolites, such as sAPPα. In cell lysates, APP levels were increased and APP was found to interact with ER-chaperones in a perinuclear region, as determined by co-immunoprecipitation and fluorescence microscopy studies. Lactic acid had only a very modest effect on cellular pH, did increase the levels of ER chaperones Grp78 and Grp94 and led to APP aggregate formation reminiscent of aggresomes.
CONCLUSIONS/SIGNIFICANCE: These findings suggest that sustained elevations in lactic acid levels could be a risk factor in amyloidogenesis related to Alzheimer's disease through enhanced APP interaction with ER chaperone proteins and aberrant APP processing leading to increased generation of amyloid peptides and APP aggregates.
乳酸是糖酵解的天然副产物，当线粒体功能受损、能量需求高、氧气供应不足时，会过量产生。阿尔茨海默病β-淀粉样肽（Aβ）产生所涉及的酶，BACE1，在较低的 pH 值下最佳发挥作用，这促使我们研究乳酸在淀粉样前体蛋白（APP）加工中的潜在作用。
方法/主要发现：乳酸可通过 ELISA 测量，增加人神经母细胞瘤细胞（SH-SY5Y）培养物中 Aβ40 和 Aβ42 的水平，而降低 sAPPα 等 APP 代谢物。通过共免疫沉淀和荧光显微镜研究发现，在细胞裂解物中，APP 水平增加，并且 APP 与内质网伴侣蛋白在核周区域相互作用。乳酸对细胞 pH 的影响非常小，但可增加内质网伴侣蛋白 Grp78 和 Grp94 的水平，并导致 APP 聚集形成类似于聚集物的结构。
结论/意义：这些发现表明，乳酸水平持续升高可能是与阿尔茨海默病相关的淀粉样蛋白形成的一个风险因素，通过增强 APP 与内质网伴侣蛋白的相互作用以及异常的 APP 加工，导致淀粉样肽和 APP 聚集物生成增加。
