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MicroRNA-195 rescues ApoE4-induced cognitive deficits and lysosomal defects in Alzheimer’s disease pathogenesis

Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP(2)) 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/PIP(2) pa...

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Detalles Bibliográficos
Autores principales: Cao, Jiqing, Huang, Min, Guo, Lei, Zhu, Li, Hou, Jianwei, Zhang, Larry, Pero, Adriana, Ng, Sabrina, El Gaamouch, Farida, Elder, Gregory, Sano, Mary, Goate, Alison, TCW, Julia, Haroutunian, Vahram, Zhang, Bin, Cai, Dongming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785685/
https://www.ncbi.nlm.nih.gov/pubmed/32632205
http://dx.doi.org/10.1038/s41380-020-0824-3
Descripción
Sumario:Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP(2)) 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/PIP(2) 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 PIP(2)-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 PIP(2) dyshomeostasis, cognitive deficits, and AD pathology.