MicroRNA-195 rescues ApoE4-induced cognitive deficits and lysosomal defects in Alzheimer‚Äôs disease pathogenesis
Authors: Sabrina Ng
Min Huang
Gregory Elder
Jiqing Cao
Adriana Pero
Vahram Haroutunian
Lei Guo
Mary Sano
Farida El Gaamouch
Julia Tcw
Dongming Cai
Larry Zhang
Jianwei Hou
Li Zhu
Bin Zhang
Alison Goate
Journal: Molecular Psychiatry (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Apolipoprotein E4; miR-195; Alzheimer's Disease; brain phosphoinositol biphosphate; cognitive impairment
Affiliations: James J Peters VA Medical Center, Research & Development, Bronx, NY, 10468, USA., Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Cornell University, Ithaca, NY, 14850, USA., Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Alzheimer Disease Rsearch Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., James J Peters VA Medical Center, MIRECC, Bronx, NY, 10468, USA., James J Peters VA Medical Center, Research & Development, Bronx, NY, 10468, USA. ., Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ., Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ., Alzheimer Disease Rsearch Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ., Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .

Abstract:  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. 

Retracted: No

PubPeer comments:
  The graphs of flow cytometry in Figure 4B in the red boxes were much more similar than expected. Apparently they are from different groups. Please check! ,