Calcium/calmodulin-dependent protein kinase kinase β is neuroprotective in stroke in aged mice.
Stroke is a devastating neurological disease and the leading cause of long-term disability, particularly in the elderly. Calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) is a major kinase activated by elevated levels of intracellular calcium. Our previous findings in young mice have suggested that CaMKK β is neuroprotective as KO mice had worse stroke outcomes. Because age is an important determinant of stroke outcome, we evaluated the functional role of CaMKK β in stroke in aged mice. We used middle cerebral artery occlusion to induce stroke in aged wild-type (WT) and CaMKK β KO male mice. Lentiviral vectors carrying CaMKK β (LV-CaMKK β) were used to overexpress CaMKK β in the mouse brain. Baseline levels of CaMKK β in the aged brain were significantly lower than those in young mice. LV-CaMKK β treatment reduced infarcts and neurological deficits assessed 3 days after stroke. In chronic survival experiments, CaMKK β KO mice showed increased tissue loss in the ipsilateral hemisphere 3 weeks after stroke. In addition, KO mice showed poorer functional recovery during the 3-week survival period, as measured by the rotarod test, corner test, locomotor activity assay, and novel object recognition test, compared with WT controls. The loss of blood-brain barrier proteins, inactivation of survival gene expression such as B-cell lymphoma 2 (Bcl-2) and an increase in inflammatory cytokines in the serum were observed after stroke with CaMKK β inhibition. We demonstrate that CaMKK β is neuroprotective in stroke in aged mice. Therefore, our data suggest that CaMKK β may be a potential target for reducing long-term disability after stroke.
Department of Neurology, University of Texas Health Science Center, Houston, TX, 77030, USA.|Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
Lin
L
Liu
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
Hui
H
Yuan
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
Kyle
K
Denton
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
Xue-Jun
XJ
Li
Department of Neurology, University of Texas Health Science Center, Houston, TX, 77030, USA.|Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
Louise
L
McCullough
Department of Neurology, University of Texas Health Science Center, Houston, TX, 77030, USA.|Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
Jun
J
Li
D000375:Aging; D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D018345:Mice, Knockout; D020127:Recovery of Function / Q000502:physiology; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
D002147:Calmodulin; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002118:Calcium
CaMKK; aged; stroke