Presenilin deficiency enhances tau phosphorylation and its secretion

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Neurochemistry Pub Date : 2024-07-01 DOI:10.1111/jnc.16155
Yang Sun, Sadequl Islam, Yuan Gao, Tomohisa Nakamura, Taisuke Tomita, Makoto Michikawa, Kun Zou
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Abstract

Alzheimer's disease (AD) is characterized by the accumulation of abnormally folded amyloid β-protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons. Presenilin (PS, PSEN) 1 and PS2 are essential components of γ-secretase, which is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ. PSEN mutations are associated with tau aggregation in frontotemporal dementia, regardless of the presence or absence of Aβ pathology. However, the mechanism by which PS regulates tau aggregation is still unknown. Here, we found that tau phosphorylation and secretion were significantly increased in PS double–knock-out (PS1/2−/−) fibroblasts compared with wild-type fibroblasts. Tau-positive vesicles in the cytoplasm were significantly increased in PS1/2−/− fibroblasts. Active GSK-3β was increased in PS1/2−/− fibroblasts, and inhibiting GSK3β activity in PS1/2−/− fibroblasts resulted in decreased tau phosphorylation and secretion. Transfection of WT human PS1 and PS2 reduced the secretion of phosphorylated tau and active GSK-3β in PS1/2−/− fibroblasts. However, PS1D257A without γ-secretase activity did not decrease the secretion of phosphorylated tau. Furthermore, nicastrin deficiency also increased tau phosphorylation and secretion. These results suggest that deficient PS complex maturation may increase tau phosphorylation and secretion. Thus, our studies discover a new pathway by which PS regulates tau phosphorylation/secretion and pathology independent of Aβ and suggest that PS serves as a potential therapeutic target for treating neurodegenerative diseases involving tau aggregation.

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缺乏 Presenilin 会增强 tau 的磷酸化及其分泌。
阿尔茨海默病(AD)的特征是大脑实质中异常折叠的淀粉样β蛋白(Aβ)和神经元中磷酸化的 tau 累积。Presenilin(PS,PSEN)1和PS2是γ-分泌酶的重要组成部分,γ-分泌酶负责裂解淀粉样前体蛋白(APP)生成Aβ。在额颞叶痴呆症中,无论是否存在 Aβ 病理变化,PSEN 突变都与 tau 聚集有关。然而,PS调节tau聚集的机制尚不清楚。在这里,我们发现与野生型成纤维细胞相比,PS 双基因敲除(PS1/2-/-)成纤维细胞中 tau 的磷酸化和分泌显著增加。在PS1/2-/-成纤维细胞中,细胞质中Tau阳性囊泡明显增加。PS1/2-/成纤维细胞中活性 GSK-3β 增加,抑制 PS1/2-/ 成纤维细胞中 GSK3β 的活性可减少 tau 的磷酸化和分泌。转染 WT 人 PS1 和 PS2 可减少 PS1/2-/- 成纤维细胞中磷酸化 tau 和活性 GSK-3β 的分泌。然而,没有γ-分泌酶活性的PS1D257A并没有减少磷酸化tau的分泌。此外,尼克蛋白缺乏也会增加 tau 的磷酸化和分泌。这些结果表明,PS复合物成熟不足可能会增加tau的磷酸化和分泌。因此,我们的研究发现了一种独立于Aβ的PS调节tau磷酸化/分泌和病理学的新途径,并表明PS是治疗涉及tau聚集的神经退行性疾病的潜在治疗靶点。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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