Journal
MOLECULAR PSYCHIATRY
Volume 26, Issue 9, Pages 4687-4701Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-020-0824-3
Keywords
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Funding
- NIH [1R01AG048923, RF1AG054014, R56AG058655, AD062683, UO1AG046170, RF1AG057440, UO1AG052411]
- Department of Veteran Affairs [I01BX003380, I01RX002290, IO1RX002660, I01CX000619]
- James J. Peters VA Medical Center Research Core Facilities
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miR-195 is closely associated with ApoE4-related brain PIP(2) dyshomeostasis, cognitive deficits, and AD pathology.
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/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 ofApoE4(+/-)patients with clinical diagnosis of mild cognitive impairment (MCI) or early AD when compared toApoE4(-/-)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 inApoE4(+/+)mouse hippocampal brain tissue and cultured neurons when compared toApoE3(+/+)counterparts. Over-expressing miR-195 reduces expression levels of its top predicted targetsynaptojanin 1(synj1), a brain PIP2-degrading enzyme. Furthermore, elevating miR-195 ameliorates cognitive deficits, amyloid plaque burden, and tau hyper-phosphorylation inApoE4(+/+)mice. In addition, elevating miR-195 rescues AD-related lysosomal defects in inducible pluripotent stem cells (iPSCs)-derived brain cells ofApoE4(+/+)AD subjects while inhibiting miR-195 exacerbates these phenotypes. Together, our data uncover a novel regulatory mechanism of miR-195 targeted atApoE4-associated brain PIP(2)dyshomeostasis, cognitive deficits, and AD pathology.
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