Vascular cognitive impairment and dementia (VCID), a type of cognitive disorder mainly induced by
cerebrovascular pathology and dysfunction, is widely recognized as the second most common cause of
dementia after Alzheimer’s disease, and results in tremendous economic and social burdens on our society.
Despite recent progress in VCID research, our understanding of cerebrovascular contributions to the
pathogenesis of VCID is still limited, and the effective therapeutic approaches for VCID are unavailable.
Long non-coding RNAs (lncRNAs) function as a novel class of noncoding RNAs that modulate gene or
protein expression. Cumulative studies have documented that lncRNAs are involved in many important
biological processes as well as implicated in regulating the pathogenesis of cerebrovascular diseases.
However, the functional significance and molecular mechanisms of lncRNA molecules in regulating
cerebrovascular pathogenesis and the progression of cognitive decline are totally unknown in VCID.
In our recent preliminary studies, we have shown that the expression of a lncRNA, metastasis associated
lung adenocarcinoma transcript 1 (Malat1), is significantly increased in mouse cerebral vasculature after
chronic cerebral hypoperfusion (CCH)-induced VCID. Of note, genetic deletion of Malat1 displayed increased
cognitive impairment, white matter injury, and neuronal loss in the experimental VCID mouse model, whereas
EC-selective Malat1 transgenic overexpression resulted in reduced cognitive impairment. Mechanistically, we
have documented that Malat1 genetic deficiency increased BBB permeability in mice after VCID. Moreover,
loss-of-Malat1 function by LNA-GapmeR significantly increased proinflammatory cytokines (MCP-1, E-selectin)
and reduced the expression of VE-cadherin and ZO-1 in primary brain microvascular endothelial cells (BMECs)
after oxygen-glucose deprivation (OGD). These findings have provided the basis for our Central Hypothesis
that vascular Malat1 ameliorates white and grey matter injury and inhibits long-term cognitive decline
in CCH-induced VCID through maintaining BBB integrity and reducing endothelial inflammation to
improve the brain microenvironment. Three specific aims will be performed in this proposal. Aim 1: Define
the role of vascular Malat1 in long-term cognitive disorders, brain white matter injury, and neuronal loss in
experimental VCID; Aim 2: Elucidate the mechanisms of vascular Malat1-mediated brain protection in VCID;
Aim 3: Explore systematic delivery of the Malat1 activator polydatin as a potential therapy in VCID. Elucidating
Malat1 cerebrovascular protection will enable us to discover the vascular contribution to brain white and grey
matter injury and dementia, and lead us to develop novel and effective lncRNA-based treatment against VCID.
