Presenilin 1 deficiency impairs Aβ42-to-Aβ40- and angiotensin-converting activities of ACE.
Presenilin 1 deficiency impairs Aβ42-to-Aβ40- and angiotensin-converting activities of ACE.
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DOI：
10.3389/fnagi.2023.1098034
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发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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阿尔茨海默病（AD）与脑中淀粉样β蛋白1 - 42（A β 42）积累有关。A β 42和A β 40是淀粉样前体蛋白产生的两种主要物质。我们发现血管紧张素转换酶（ACE）以ACE结构域和糖基化依赖性方式将神经毒性A β 42转化为神经保护性A β 40。早老素1（Presenilin 1，PS1）突变是家族性AD的主要致病基因，并导致A β 42/40比值升高。然而，PSEN1突变诱导A β 42/40比值升高的机制尚不清楚。我们在小鼠野生型和PS1缺陷型成纤维细胞中过度表达人ACE。纯化的ACE蛋白用于分析A β 42-至-A β 40-和血管紧张素转换活性。免疫荧光染色法检测血管紧张素转换酶的分布。我们发现，与野生型成纤维细胞的ACE相比，从PS1缺陷型成纤维细胞纯化的ACE显示出糖基化改变，并显著降低了A β 42向A β 40和血管紧张素转化的活性。在PS1缺陷的成纤维细胞中，野生型PS1的过表达恢复了ACE的A β 42至A β 40和血管紧张素转换活性。有趣的是，PS1突变体完全恢复了PS1缺陷型成纤维细胞的血管紧张素转换活性，但一些PS1突变体不能恢复A β 42至A β 40的转换活性。我们还发现，成年小鼠脑中ACE的糖基化与胚胎脑中的不同，并且成年小鼠脑中A β 42转化为A β 40的活性低于胚胎脑。PS1缺乏改变了ACE的糖基化，并损害了其A β 42-向A β 40-和血管紧张素转化的活性。我们的研究结果表明，PS1缺陷和PSEN1突变通过降低ACE的A β 42转化为A β 40的活性来增加A β 42/40的比例。
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 PSEN1 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 PSEN1 mutations increase the Aβ42/40 ratio by reducing the Aβ42-to-Aβ40-converting activity of ACE.
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影响因子：
3.7
作者：
Kryukova OV;Tikhomirova VE;Golukhova EZ;Evdokimov VV;Kalantarov GF;Trakht IN;Schwartz DE;Dull RO;Gusakov AV;Uporov IV;Kost OA;Danilov SM
通讯作者：
Danilov SM
影响因子：
5.4
作者：
De Strooper, Bart;Iwatsubo, Takeshi;Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.
DOI：
10.1073/pnas.1511175112
发表时间：
2015-11-24
影响因子：
11.1
作者：
Goth, Christoffer K.;Halim, Adnan;Schjoldager, Katrine T. -B. G.
通讯作者：
Schjoldager, Katrine T. -B. G.
影响因子：
10.5
作者：
Donoviel, DB;Hadjantonakis, AK;Bernstein, A
通讯作者：
Bernstein, A
影响因子：
4.8
作者：
Fernandez, Marty A.;Klutkowski, Julia A.;Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.