Regulatory microRNAs and vascular cognitive impairment and dementia

Abstract

Vascular cognitive impairment and dementia (VCID) is defined as a progressive dementia disease related to cerebrovascular injury and often occurs in aged populations. Despite decades of research, effective treatment for VCID is still absent. The pathological processes of VCID are mediated by the molecular mechanisms that are partly modulated at the post-transcriptional level. As small endogenous non-coding RNAs, microRNAs (miRs) can regulate target gene expression through post-transcriptional gene silencing. miRs have been reported to play an important role in the pathology of VCID and have recently been suggested as potential novel pharmacological targets for the development of new diagnosis and treatment strategies in VCID. In this review, we summarize the current understanding of VCID, the possible role of miRs in the regulation of VCID and attempt to envision future therapeutic strategies. Since manipulation of miR levels by either pharmacological or genetic approaches has shown therapeutic effects in experimental VCID models, we also emphasize the potential therapeutic value of miRs in clinical settings.

Keywords: aging; dementia; microRNAs; regulatory mechanisms; vascular cognitive impairment.

Figure 1

Potential molecular mechanisms in VCID. CCH can cause a cascade of pathological changes: neuronal damage, WM lesions, glial activation, and BBB disruption, resulting in cognitive impairment and dementia in experimental studies. The following cellular hemostasis abnormalities mainly contribute to the above pathological changes in VCID: oxidative stress, neuroinflammation, BBB disruption, abnormal lipoprotein metabolism, endoplasmic reticulum stress, and the deposition of Aβ

Figure 2

miR regulatory mechanisms in experimental VCID. miR‐132, miR‐9, and miR‐124 can regulate oxidative stress by the CREB pathway, and miR‐195 can inhibit the deposition of Aβ in neurons. miR‐181c, miR‐9, miR‐124, miR‐210‐5p, miR‐134‐5p, miR‐132, and miR‐153 can regulate synaptic loss by AKT/GSK3β and other signaling pathways in neuron dendrites. miR‐26b, miR‐126, and miR‐93 can regulate neuroinflammation. miR‐96 and miR‐27a can suppress autophagy in neurovascular units. miR‐501‐3p can decrease tight junction expression in white matter and the blood‐brain barrier

Figure 3

miR‐based therapy in experimental VCID. There are two therapeutic strategies to treat VCID with miR mediators: restoring downregulated miRs by using miR mimics (Green) or blocking upregulated miRs by applying their antagomirs (Red)