| Popis: |
Background Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population provides evidence for micro-infracts and micro-bleeds, which contribute to vascular dementia. Such vascular insult may be caused by impairment in blood flow in specific area in brain involving small vessels and these could 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 on cognition specifically, memory impairment. The molecular underpinnings were also studied to comprehend the commonalities between vascular dementia and Alzheimer’s disease. Methods Vascular constriction was achieved by bilateral injection of ET-1 (Endothelin − 1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impact on endothelial cells lining of blood vessels was examined by staining for CD31, a marker of endothelial cells. Contextual fear conditioning, Novel object recognition and Morris water maze task was performed to ascertain associative learning and spatial memory deficits. Activity dependent protein translation, which is dependent on Akt1-mTOR signaling was also examined since this is critical for synaptic plasticity. Results There was considerable decrease in CD31 expression in endothelial cells lining the blood vessels around the hippocampal region. The impediment in cerebral blood flow following ET-1 injection lead to deficits in associative learning and spatial memory after 7 days. Activity dependent protein translation, which is critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue of endothelin injected mice. Further, Akt1- mTOR signaling cascade was downregulated due to decreased Akt1 phosphorylation indicating that this could be the 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. Conclusions Vasoconstriction caused by bilateral injection of ET-1 leads to prominent associative and spatial memory deficit. Decline in activity dependent protein translation in hippocampus and loss of Akt1-mTOR signaling demonstrates potential molecular mechanism impacting synaptic plasticity during vasoconstriction akin to early deficits in AD mice. |
