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

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.

Lentivirus-Carried microRNA-195 Rescues Memory Deficits of Alzheimer’s Disease Transgenic Mouse by Attenuating the Generation of Amyloid Plaques

“…Although many new drugs have been developed to treat AD, many clinical trials of monotherapy treatments have failed to affect disease progression or symptoms compared with placebo ( Godyn et al, 2016 ; Cummings et al, 2019 ). It has been reported that up-regulating miR-195 could improve cognitive decline of CBH rats and ApoE4 +/+ mice by targeting multiple genes ( Ai et al, 2013 ; Cao et al, 2020 ). However, if miR-195 could effectively rescue the impaired cognition APP/PS1 transgenic mouse, an acknowledged animal model used for Aβ-related drug screening, is not yet reported.…”

“…MiRNAs are multi-target RNAs that are considered to be promising biomarkers and therapeutics for a variety of diseases ( Lu and Thum, 2019 ; Brennan and Henshall, 2020 ). A series of previous studies have shown that miR-195 is involved in dementia-related pathological processes by targeting multiple genes ( Ai et al, 2013 ; Sun et al, 2015 ; Liu et al, 2016 ; Chen et al, 2017 ; Cao et al, 2020 ; Mao et al, 2020 ) and up-regulation of miR-195 in the hippocampus and cortex could improve the cognitive function of CBH rats ( Ai et al, 2013 ) and ApoE4 +/+ mice ( Cao et al, 2020 ). Furthermore, clinical studies have reported that miR-195 level is decreased in the brain of patients with acute ischemic stroke ( Yang et al, 2018 ) and in the serum of patients with vascular dementia (VaD) ( Ai et al, 2013 ).…”

“…They are considered as drug targets for the RNA-based therapeutic strategies ( Lu and Thum, 2019 ; Revia et al, 2019 ; Brennan and Henshall, 2020 ). Our previous study found that microRNA-195 ( miR-195 ) was down-regulated in the hippocampus and cortex of rats suffering from chronic brain hypoperfusion (CBH) ( Ai et al, 2013 ), which was recently verified in the brain tissue of patients with the clinical diagnosis of mild cognitive impairment (MCI) ( Cao et al, 2020 ). Thereafter, a series of studies demonstrated that down-regulation of miR-195 targets multiple genes and participates in a variety of pathological processes under CBH status by up-regulating APP and BACE1 ( Ai et al, 2013 ); promoting hyperphosphorylation of Tau by increasing p35 level and activating calpain to accelerate the conversion of CDK5/p35 to CDK5/p25; inactivating PP2A by elevating PME-1expression to inhibit methylation level of PP2A C at Leu309 residue ( Sun et al, 2015 ; Liu et al, 2016 ); facilitating dendritic remodeling and neuron death through promoting N-APP expression and post-transcriptionally up-regulating DR6 which could induce the activation of caspases 3 and 6 ( Chen et al, 2017 ).…”

“…Thereafter, a series of studies demonstrated that down-regulation of miR-195 targets multiple genes and participates in a variety of pathological processes under CBH status by up-regulating APP and BACE1 ( Ai et al, 2013 ); promoting hyperphosphorylation of Tau by increasing p35 level and activating calpain to accelerate the conversion of CDK5/p35 to CDK5/p25; inactivating PP2A by elevating PME-1expression to inhibit methylation level of PP2A C at Leu309 residue ( Sun et al, 2015 ; Liu et al, 2016 ); facilitating dendritic remodeling and neuron death through promoting N-APP expression and post-transcriptionally up-regulating DR6 which could induce the activation of caspases 3 and 6 ( Chen et al, 2017 ). Furthermore, elevating miR-195 ameliorated cognitive deficits, amyloid plaque burden, and tau hyper-phosphorylation in ApoE4 (+/+) mice and rescued AD-related lysosomal defects in inducible pluripotent stem cells (iPSCs)-derived brain cells of ApoE4 (+/+) AD patients, while inhibiting miR-195 exacerbated these phenotypes by targeting synaptojanin 1 (synj1) ( Cao et al, 2020 ). These results suggest that miR-195 might be a potential multi-target drug to prevent or treat AD at the early stage.…”

Epigenetics: Recent Advances and Its Role in the Treatment of Alzheimer's Disease

“…MicroRNA-326 decreases tau hyperphosphorylation and improves cognitive functions of AD through the JNK signaling pathway (130). Elevating the levels of microRNA-195 diminishes tau hyperphosphorylation and Aβ burden in ApoE4 +/+ mice (131). Furthermore, some altered microRNAs are directly related to APP or Aβ processing in AD.…”