Gao Yuan, Sun Yang, Islam Sadequl, Nakamura Tomohisa, Tomita Taisuke, Zou Kun, Michikawa Makoto
Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
Laboratory of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo, Japan.
Front Aging Neurosci. 2023 Feb 17;15:1098034. doi: 10.3389/fnagi.2023.1098034. eCollection 2023.
Alzheimer's disease (AD) is associated with amyloid β-protein 1-42 (Aβ42) accumulation in the brain. Aβ42 and Aβ40 are the major two species generated from amyloid precursor protein. We found that angiotensin-converting enzyme (ACE) converts neurotoxic Aβ42 to neuroprotective Aβ40 in an ACE domain- and glycosylation-dependent manner. Presenilin 1 (PS1) mutations account for most of cases of familial AD and lead to an increased Aβ42/40 ratio. However, the mechanism by which mutations induce a higher Aβ42/40 ratio is unclear.
We over expressed human ACE in mouse wild-type and PS1-deficient fibroblasts. The purified ACE protein was used to analysis the Aβ42-to-Aβ40- and angiotensin-converting activities. The distribution of ACE was determined by Immunofluorescence staining.
We found that ACE purified from PS1-deficient fibroblasts exhibited altered glycosylation and significantly reduced Aβ42-to-Aβ40- and angiotensin-converting activities compared with ACE from wild-type fibroblasts. Overexpression of wild-type PS1 in PS1-deficient fibroblasts restored the Aβ42-to-Aβ40- and angiotensin-converting activities of ACE. Interestingly, PS1 mutants completely restored the angiotensin-converting activity in PS1-deficient fibroblasts, but some PS1 mutants did not restore the Aβ42-to-Aβ40-converting activity. We also found that the glycosylation of ACE in adult mouse brain differed from that of embryonic brain and that the Aβ42-to-Aβ40-converting activity in adult mouse brain was lower than that in embryonic brain.
PS1 deficiency altered ACE glycosylation and impaired its Aβ42-to-Aβ40- and angiotensin-converting activities. Our findings suggest that PS1 deficiency and mutations increase the Aβ42/40 ratio by reducing the Aβ42-to-Aβ40-converting activity of ACE.
阿尔茨海默病（AD）与大脑中淀粉样β蛋白1-42（Aβ42）的积累有关。Aβ42和Aβ40是由淀粉样前体蛋白产生的主要两种类型。我们发现血管紧张素转换酶（ACE）以一种依赖于ACE结构域和糖基化的方式将神经毒性Aβ42转化为神经保护性Aβ40。早老素1（PS1）突变占大多数家族性AD病例，并导致Aβ42/40比率增加。然而，突变导致更高Aβ42/40比率的机制尚不清楚。
我们在小鼠野生型和PS1缺陷型成纤维细胞中过表达人ACE。纯化的ACE蛋白用于分析Aβ42向Aβ40的转化以及血管紧张素转换活性。通过免疫荧光染色确定ACE的分布。
我们发现，与野生型成纤维细胞来源的ACE相比，从PS1缺陷型成纤维细胞中纯化的ACE表现出糖基化改变，并且Aβ42向Aβ40的转化以及血管紧张素转换活性显著降低。在PS1缺陷型成纤维细胞中过表达野生型PS1可恢复ACE的Aβ42向Aβ4
