Abstract
Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. In the present study we developed a transient model of vaso-constriction to study the impact of such pathology by bilateral injection of ET-1 (Endothelin-1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impediment in cerebral blood flow decreased CD31 expression in endothelial cells lining the blood vessels around the hippocampal region, leading to memory deficits after 7 days. Activity dependent protein translation, critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue. Further, Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation. However, these effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. Present study demonstrates that vasoconstriction leading to memory deficit and decline in activity dependent protein translation in hippocampus as a potential molecular mechanism impacting synaptic plasticity.
Highlights
Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia
To find out whether loss of CD31 expression lead to Blood Brain Barrier (BBB) leakage we stained sections from early and late time points for blood derived IgG followed by isolectin staining for topography of vessels
Activity dependent protein translation in hippocampal synaptoneurosomes from mice treated with ET-1 for 30 days was similar to vehicle controls (Sup Fig. 6E). These results indicate that vascular homeostasis is reestablished within 30 days after ET-1treatment restored Akt-mTOR signaling players Akt-1 (Sup Fig. 7 A, B, E & F), GSK (Sup Fig. 7 I & J), mTOR (Sup Fig. 7 C & D) and downstream molecules like S6K as well as 4EBP1 leading to reversal of the memory deficits (Sup Fig. 7 G, H, K & L)
Summary
Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation These effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. ET-1 into lateral ventricles caused vasoconstriction around hippocampal region as observed by decreased CD31 (cluster of differentiation 31) expression, a marker for endothelial cells lining the blood vessels
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