MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion

Abstract

Background: Chronic brain hypoperfusion (CBH) is closely related to Alzheimer's disease (AD) and vascular dementia (VaD). Meanwhile, synaptic pathology plays a prominent role in the initial stage of AD and VaD. However, whether and how CBH impairs presynaptic plasticity is currently unclear. Methods: In the present study, we performed a battery of techniques, including primary neuronal culture, patch clamp, stereotaxic injection of the lentiviral vectors, morris water maze (MWM), dual luciferase reporter assay, FM1-43 fluorescence dye evaluation, qRT-PCR and western blot, to investigate the regulatory effect of miR-153 on hippocampal synaptic vesicle release both in vivo and in vitro. The CBH rat model was generated by bilateral common carotid artery ligation (2VO). Results: Compared to sham rats, 2VO rats presented decreased field excitatory postsynaptic potential (fEPSP) amplitude and increased paired-pulse ratios (PPRs) in the CA3-CA1 pathway, as well as significantly decreased expression of multiple vesicle fusion-related proteins, including SNAP-25, VAMP-2, syntaxin-1A and synaptotagmin-1, in the hippocampi. The levels of microRNA-153 (miR-153) were upregulated in the hippocampi of rats following 2VO surgery, and in the plasma of dementia patients. The expression of the vesicle fusion-related proteins affected by 2VO was inhibited by miR-153, elevated by miR-153 inhibition, and unchanged by binding-site mutation or miR masks. FM1-43 fluorescence images showed that miR-153 blunted vesicle exocytosis, but this effect was prevented by either 2′-O-methyl antisense oligoribonucleotides to miR-153 (AMO-153) and miR-masking of the miR-153 binding site in the 3′ untranslated region (3'UTR) of the Snap25, Vamp2, Stx1a and Syt1 genes. Overexpression of miR-153 by lentiviral vector-mediated miR-153 mimics (lenti-pre-miR-153) decreased the fEPSP amplitude and elevated the PPR in the rat hippocampus, whereas overexpression of the antisense molecule (lenti-AMO-153) reversed these changes triggered by 2VO. Furthermore, lenti-AMO-153 attenuated the cognitive decline of 2VO rats.

Cholinergic Dysfunction Involvement in Chronic Cerebral Hypoperfusion-Induced Impairment of Medial Septum–dCA1 Neurocircuit in Rats

“…CCH is considered to be the preclinical stage of mild cognitive impairment (Du et al, 2017 ); and it has already been proved to participate in the β-amyloid deposition, tau phosphorylation, neuronal death, impairment of hippocampal pre-synaptic plasticity, and theta oscillation in rats (Ai et al, 2013 ; Sun et al, 2015 ; Liu et al, 2016 ; Chen et al, 2017 ; Li et al, 2019 ; Yan et al, 2020 ). However, as the largest cholinergic nucleus and the theta generator of brain, whether the function of MS could be impaired by CCH is still unelucidated.…”

“…Transient forebrain ischemia following occlusion of the vertebral and common carotid arteries was reported inducing glutamate excitotoxicity and free radical formation (Gottlieb et al, 2006 ), and the hippocampal fEPSPs of CA3-CA1 circuit were found to be damaged due to impaired glutamatergic vesicle trafficking and vesicle release in CCH rat model (Yan et al, 2020 ; Zhang et al, 2020 ). These results suggested that impaired glutamatergic function might be the common feature in both acute and chronic brain ischemia.…”

“…Chronic cerebral hypoperfusion (CCH) is considered a common cause of sporadic AD and vascular dementia (VaD; Cole and Vassar, 2009 ; Gorelick et al, 2011 ; Honjo et al, 2012 ) and a subclinical state of moderate cognitive impairment (Maalikjy Akkawi et al, 2005 ; Ruitenberg et al, 2005 ; Gorelick et al, 2011 ). Many previous studies have reported that CCH induces cognitive decline by trigging a variety of hippocampal pathologies, including β-amyloid deposition (Ai et al, 2013 ; ElAli et al, 2013 ), tau phosphorylation (Sun et al, 2015 ; Liu et al, 2016 ; Raz et al, 2019 ), neuronal death (Chen et al, 2017 ), and even impairment of hippocampal pre-synaptic plasticity (Yan et al, 2020 ). However, it is still unknown whether and how CCH initiates the impairment of basal forebrain–hippocampal neurocircuit.…”

Regulatory microRNAs and vascular cognitive impairment and dementia

“…Virus‐mediated delivery of miR‐181c partially rescued cognitive impairment in rat CCH 108 . Direct knockdown of miR‐153 or overexpression of the antisense molecule (lenti‐AMO‐153) may be a new strategy for alleviating the synaptic pathology and cognitive decline of VaD 109,110 …”

“…Considering the critical role of miR‐195 in VCID, the complement of exogenous miR‐195 may be a potentially anti‐dementia approach. A recent report showed that miR‐153 is involved in the CCH‐impaired hippocampal glutamatergic synaptic vesicle trafficking by binding site in the 3′ untranslated region (3’UTR) of the SYN1, Snap25, Vamp2, Stx1a, and Syt1 genes, which may be a new drug target for prevention or treatment of AD and VaD 109,110 …”