Abstract P761: Reducing Reactive Astrocytes Improves Cognitive Function in a Mouse Model of Vascular Cognitive Impairment and Dementia

Abstract

Inflammation and reactive astrocytes are pathologic features in vascular cognitive impairment and dementia (VCID). However, there are no effective therapies to reduce chronic hypoperfusion-induced reactive astrocytes and neuroinflammation and cognitive deficits in VCID. Activation of Na + /H + exchanger 1 (NHE1) in astrocytes mediates Na + influx in exchange of H + efflux, causing hypertrophy and swelling of reactive astrocytes after acute brain injury. Whether pharmacological blockade of NHE1 protein can reduce reactive astrocytes and improve cognitive deficits remains untested. Bilateral carotid artery stenosis (BCAS) with microcoils as a murine VCID model was induced in adult male C57BL/6 mice. BCAS procedures led to sustained reduction (30-40%) in cerebral blood flow (CBF) and deficits in special working memory by 30 days post-surgery (p < 0.05). Compared with sham control mice, BCAS mice displayed demyelination in corpus callosum (CC) and external capsule (EC) at 30 days post-surgery (p < 0.05). There were significantly increased GFAP + astrocytes and Iba1 + microglia in CC, EC and hippocampus in BCAS brain at 30 days post-surgery (p < 0.05). Interestingly, those GFAP + astrocytes and Iba1 + microglia exhibited elevated NHE1 protein expression in these brain regions (p < 0.05). These results suggest that NHE1 protein may play a role in chronic hypoperfusion-induced reactive astrocyte transformation and microglia activation. We administered saline vehicle (Veh) or NHE1 inhibitor HOE642 during 30 days post-BCAS (via either i.p. or osmotic mini-pump). The Veh- and HOE642-treated BCAS mice caused similar reduction in CBF. Compared to the Veh controls, both HOE642 treatment regimens significantly improved cognitive performance at 30 days post-surgery (p < 0.05). Causative relationship between blockade of NHE1 protein activation and reducing glia-mediated inflammation and demyelination are under investigation by immunostaining assessments and ex-vivo MRI DTI analysis. Taken together, our study suggests that elevation of NHE1 protein activity plays a role in glial activation in the murine VCID model. Pharmacological blockade of NHE1 protein shows efficacy in reducing cerebral hypoperfusion-induced chronic brain injury and cognitive impairment.