Role of microRNA-126 in vascular cognitive impairment in mice

Abstract

Vascular dementia (VaD) affects cognition and memory. MicroRNA-126 (miR-126) is an angiogenic microRNA that regulates vascular function. In this study, we employ a multiple microinfarction (MMI) model to induce VaD in mice, and investigate VaD-induced cognitive dysfunction, white matter (WM) damage, glymphatic dysfunction and the role of miR-126 in mediating these effects. Male six-to eight-months old C57/BL6 mice (WT) were subject to MMI model, and cerebral blood flow (CBF), vessel patency, glymphatic function, cognitive function, and serum miR-126 expression were measured. Mice were sacrificed at 28 days after MMI. To investigate the role of miR-126 in VaD, cognitive function, water channel integrity and glymphatic function were assessed in male, six-to eight months old conditional-knockout endothelial cell miR-126 (miR-126), and control (miR-126) mice. MMI in WT mice induces significant cognitive deficits, decreases CBF and vessel patency; evokes astrocytic and microglial activation, increases inflammation, axonal/WM damage; decreases synaptic plasticity and dendritic spine density, instigates water channel and glymphatic dysfunction, and decreases serum miR-126 expression. MiR-126 mice exhibit significant cognitive impairment, decreased CBF, myelin density and axon density, increased inflammation, and significant water channel and glymphatic dysfunction compared to miR-126 mice. Reduction of endothelial miR-126 expression may mediate cognitive impairment in MMI-induced VaD.

Subdural haematomas drain into the extracranial lymphatic system through the meningeal lymphatic vessels

“…*P < 0.05, ** P < 0.01, NS P > 0.05, n = 4/group subdural cavity to the peripheral circulation was not completely ruled out in this work, the decreased drainage efficacy after cervical lymphatic vessel ligation strongly indicates that a direct pathway from the mLVs to the extracranial lymphatic system plays a key role in intracranial waste clearance. Because the lymphatic system is independent of the circulation, this new finding of an intracranial-extracranial lymphatic drainage pathway also provides a reasonable explanation for the lack of inflammatory reactions during clinical CSDH formation and atorvastatin-driven haematoma elimination [36,40].…”

“…CSDH is predicted to be one of the most common neurosurgical diseases, especially in individuals over 70 years old [21,27,28]. It has been demonstrated that CSDH can be absorbed spontaneously and that atorvastatin can promote this process [35,40]. Despite the presence of multitudinous and dense inflammatory cytokines in CSDHs, only a few patients have demonstrated systemic inflammatory responses that include fever and increased white blood cell counts during the process of haematoma absorption [11,19,26], and most CSDH patients present with mild neurological symptoms [17].…”

HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia

“…Previously, we have found that mice subjected to MMI have significantly decreased miR-126 expression which may play a key role in mediating cognitive impairment after MMI (Yu et al, 2019). Also, mice with endothelial miR-126 knockdown exhibited significant cognitive dysfunction, reduced CBF, WM rarefaction including decreased myelin and axon density, increased inflammation and glial activation, and significant glymphatic dysfunction (Yu et al, 2019). We have previously demonstrated that HUCBC treatment increases miR-126 expression and improves functional outcome, promotes WM remodeling, and reduces inflammation after stroke in diabetic mice (Chen et al, 2016).…”

“…Also, HUCBC transplantation is safe and well-tolerated in human patients with AD in the Phase 1 clinical trial (Kim et al, 2015). In our previous study, we reported that mice subjected to MMI have significantly decreased miR-126 expression, and mice with endothelial miR-126 knockdown exhibit significant cognitive impairment, WM injury, and glymphatic dysfunction (Yu et al, 2019). MiRs, and particularly miR-126, are emerging as key players in the pathogenesis of vascular damage (Zampetaki et al, 2010).…”

MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models

“…While the angiogenic miRNA, miR‐126, is a regulator of vascular function, its serological level was declined following VD. Downregulation of miR‐126 in the VD mice model coincides with higher inflammation, glymphatic and water channel dysfunction, lower myelin and axon density, and worsened cognitive function and cerebral blood flow (Yu et al, 2019). Ragusa et al (2016) revealed a reduction in the levels of miR‐10b‐3p, miR29a‐3p, and miR‐130b‐3p in VD sufferers compared to control individuals.…”