Abstract 12352: Apoptosis Signal-Regulating Kinase 1 is a Novel Therapeutic Target Molecule for Vascular Dementia
Background: Hypertension leads to cognitive decline due to chronic cerebral ischemia in white matter (WM). We previously reported that apoptosis signal-regulating kinase 1 (ASK1) is a key molecule involved in vascular endothelial dysfunction. This study was undertaken to test the hypothesis that ASK1 has a key role in cognitive decline induced by chronic cerebral ischemia.
Methods: Chronic cerebral ischemia in WM was induced by bilateral common carotid artery stenosis (BCAS) with microcoils (inner diameter; 0.16mm) in C57BL/6J wild type (WT) and ASK1 deficient (ASK1-/-) mice. We evaluated spatial working memory as a cognitive function at 3 weeks after BCAS by assessing spontaneous alteration behavior on the Y-maze test. We measured WM lesion utilizing Kluver-Barrera staining. Evans blue (1%) was injected intraperitoneally to mice at 3 days after BCAS and extravasated Evans blue in WM was measured under fluorescent microscopy to evaluate BBB breakdown.
Results: Using a laser speckle blood flow imager, BCAS significantly and equally lowered the cerebral blood flow of WT and ASK1-/- mice, compared to the sham groups. There were no significant differences in blood pressure in either strain of mice after BCAS. Phosphorylation of ASK1 and its downstream molecules, p38 and c-Jun N-terminal kinase, in the brains of WT mice persistently increased after BCAS. BCAS significantly caused cognitive decline (spontaneous alteration behavior: BCAS Group [43%] vs Sham Group [56%]; p<0.01) and progression of WM lesion (BCAS Group [Grade 1.3±0.2] vs Sham Group [Grade 0.2±0.8]; p<0.01) in WT mice at 3 weeks while BCAS did not cause them in ASK1-/- mice. Cerebral mRNA levels of tumor necrosis factor-α and monocyte chemoattractant protein-1 were increased in WT mice subjected to BCAS, whereas this response was not seen in ASK1-/- mice. BCAS significantly caused BBB breakdown in WT mice as shown by significant Evans blue leakage in WM. On the other hand, BCAS failed to cause BBB disruption in ASK1-/- mice.
Conclusions: Knockout of ASK1 significantly attenuated cognitive decline and WM lesions caused by chronic cerebral ischemia, through the amelioration of inflammation and BBB breakdown. ASK1 seems to be a promising novel therapeutic target molecule for vascular dementia.
- © 2011 by American Heart Association, Inc.