Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, P.R. China.
Int J Mol Med. 2010 Mar;25(3):401-7. doi: 10.3892/ijmm_00000358.
Aging is considered a high risk factor for Alzheimer's disease (AD), which is one of the most prevalent neurodegenerative disorders in the elderly population. The major pathologic feature of AD is senile plaques mainly containing amyloid-beta (Abeta) components. However, little direct evidence has shown aging in association with Abeta. Here we show that the protein-protein interaction of amyloid precursor protein (APP) and beta -site amyloid cleavage enzyme 1 (BACE1) is enhanced by the fluorescence resonance energy transfer (FRET) assay during the aging process, and the APP-BACE1 complex accumulates in the endosome in the IMR-90 fibroblast (NHF) cellular aging models. Moreover, enhanced Abeta is observed in aged cells, rat brain homogenates and human serum. Interestingly, addition of the dominant-negative mutant of Rab5, a small G-protein Rab5 involved in the endocytic process, inhibits the aging-related APP-BACE1 interaction and Abeta production, suggesting that endocytosis contributes to AD progression.
衰老是阿尔茨海默病（AD）的一个高风险因素，AD 是老年人中最常见的神经退行性疾病之一。AD 的主要病理特征是含有淀粉样蛋白-β（Abeta）成分的老年斑。然而，很少有直接证据表明衰老是与 Abeta 相关的。在这里，我们通过荧光共振能量转移（FRET）实验显示，淀粉样前体蛋白（APP）和β-位点淀粉样蛋白裂解酶 1（BACE1）的蛋白-蛋白相互作用在衰老过程中增强，并且 APP-BACE1 复合物在内体中积累在 IMR-90 成纤维细胞（NHF）的细胞衰老模型中。此外，在衰老的细胞、大鼠脑匀浆和人血清中观察到增强的 Abeta。有趣的是，添加小 G 蛋白 Rab5 的显性负突变体，Rab5 参与内吞过程，抑制与衰老相关的 APP-BACE1 相互作用和 Abeta 的产生，表明内吞作用有助于 AD 的进展。
