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

• Published in: Molecular psychiatry Vol. 26; no. 9; pp. 4687 - 4701
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2021; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/51; 13/89; 14/19; 38/1; 38/22; 38/39; 38/61; 38/77; 45/90; 631/378; 64/60; 692/699; 82/80; Aging; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides; Animals; Apolipoprotein E; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoproteins; Behavioral Sciences; Biological Psychology; Brain; Brain stem; Cerebrospinal fluid; Cognition; Cognitive ability; Cognitive Dysfunction - genetics; Development and progression; Genetic aspects; Health aspects; Hippocampus; Homeostasis; Humans; Inhibitory postsynaptic potentials; Lysosomes; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Neurodegenerative diseases; Neurosciences; Pathogenesis; Pharmacotherapy; Phenotypes; Phosphatidylinositol 4,5-diphosphate; Phosphorylation; Physiological aspects; Pluripotency; Psychiatry; Stem cell transplantation; Stem cells; Tau protein; United States
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-020-0824-3

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.