MicroRNA-195 rescues ApoE4-induced cognitive deficits and lysosomal defects in Alzheimer's disease pathogenesis.
MicroRNA-195 rescues ApoE4-induced cognitive deficits and lysosomal defects in Alzheimer's disease pathogenesis.
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MicroRNA-195挽救阿尔茨海默病发病机制中ApoE 4诱导的认知缺陷和溶酶体缺陷
DOI：
10.1038/s41380-020-0824-3
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发表时间：
2021-09
影响因子：
11
通讯作者：
Cai D
中科院分区：
文献类型：
--
作者：
Cao J;Huang M;Guo L;Zhu L;Hou J;Zhang L;Pero A;Ng S;El Gaamouch F;Elder G;Sano M;Goate A;Tcw J;Haroutunian V;Zhang B;Cai D
我们最近的发现将载脂蛋白E4 （ApoE4）在脑磷酸肌醇二磷酸（PIP2）稳态中的特异性变化与阿尔茨海默病（AD）的易感性联系起来。在本研究中，我们利用人类ROSMAP数据集和小鼠微阵列研究中的miRNA谱，确定了miR-195是参与ApoE/PIP2通路的顶级候选微rna。进一步的验证研究表明，与ApoE4−/−受试者相比，临床诊断为轻度认知障碍（MCI）或早期AD的ApoE4+/−患者的脑组织中miR-195水平显着降低。此外，脑miR-195水平随着疾病从正常衰老到早期AD的进展而降低，MCI受试者的脑脊液（CSF） miR-195水平与mini-mental status examination （MMSE）测量的认知表现呈正相关，与CSF tau水平负相关，提示miR-195参与AD的早期发展，并对认知产生潜在影响。与ApoE3+/+对照物相比，ApoE4+/+小鼠海马脑组织和培养神经元中miR-195水平也存在类似差异。过表达miR-195会降低其最高预测靶点突触连接蛋白1 （synj1）的表达水平，synj1是一种脑pip2降解酶。此外，升高miR-195可改善ApoE4+/+小鼠的认知缺陷、淀粉样斑块负担和tau过度磷酸化。此外，在ApoE4+/+ AD受试者的诱导多能干细胞（iPSCs）来源的脑细胞中，升高miR-195可挽救AD相关的溶酶体缺陷，而抑制miR-195则会加剧这些表型。总之，我们的数据揭示了miR-195针对apoe4相关的脑PIP2失衡、认知缺陷和AD病理的一种新的调控机制。
Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP2) homeostasis to the susceptibility of developing Alzheimer’s Disease (AD). In the present study, we have identified miR-195 as a top micro-RNA candidate involved in the ApoE/PIP2 pathway using miRNA profiles in human ROSMAP datasets and mouse microarray studies. Further validation studies have demonstrated that levels of miR-195 are significantly lower in human brain tissue of ApoE4+/− patients with clinical diagnosis of mild cognitive impairment (MCI) or early AD when compared to ApoE4−/− subjects. In addition, brain miR-195 levels are reduced along with disease progression from normal aging to early AD, and cerebrospinal fluid (CSF) miR-195 levels of MCI subjects are positively correlated with cognitive performances as measured by mini-mental status examination (MMSE) and negatively correlated with CSF tau levels, suggesting the involvement of miR-195 in early development of AD with a potential impact on cognition. Similar differences in miR-195 levels are seen in ApoE4+/+ mouse hippocampal brain tissue and cultured neurons when compared to ApoE3+/+ counterparts. Over-expressing miR-195 reduces expression levels of its top predicted target synaptojanin 1 (synj1), a brain PIP2-degrading enzyme. Furthermore, elevating miR-195 ameliorates cognitive deficits, amyloid plaque burden, and tau hyper-phosphorylation in ApoE4+/+ mice. In addition, elevating miR-195 rescues AD-related lysosomal defects in inducible pluripotent stem cells (iPSCs)-derived brain cells of ApoE4+/+ AD subjects while inhibiting miR-195 exacerbates these phenotypes. Together, our data uncover a novel regulatory mechanism of miR-195 targeted at ApoE4-associated brain PIP2 dyshomeostasis, cognitive deficits, and AD pathology.
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影响因子：
5.3
作者：
Goodall EF;Heath PR;Bandmann O;Kirby J;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
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Holtzman, DM
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Di Paolo, Gilbert
影响因子：
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作者：
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影响因子：
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作者：
Asai H;Ikezu S;Tsunoda S;Medalla M;Luebke J;Haydar T;Wolozin B;Butovsky O;Kügler S;Ikezu T
通讯作者：
Ikezu T