Abstract WP96: Age Related Decline Of Oligodendrogenesis After White Matter Injury

Abstract

Background and Purpose: Adult white mater retains endogenous repair mechanisms. But how aging affects this ability for self-repair remains to be fully understood. Here, we assessed the hypothesis that aged white matter loses the capacity for oligodendrogenesis, and hence is more vulnerable to external stress. Methods: A mouse model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery stenosis in young (2-month old) and middle-aged (8-month old) mice (n=30 each). White matter integrity and injury were assessed with myelin staining, myelin-basic-protein staining, and optical coherence tomography. Cognitive function was assessed by spontaneous Y-maze test. Proliferation and differentiation of oligodendrocyte precursor cells (OPCs) were evaluated using a bromodeoxyuridine assay. Results: While there was no clear difference in myelin density of the corpus callosum between young and middle-aged mice under normal conditions, the latter showed larger white matter injury and working memory deficits after chronic cerebral hypoperfusion insults (P<0.05). The numbers of newly-born oligodendrocytes and OPCs in young mice were both increased by the hypoxic stress, but these responses in middle-aged mice were lower with less activation of cAMP response element binding protein (CREB) (P<0.05). Notably, activating CREB by a type-III phosphodiesterase inhibitor cilostazol in middle-aged mice enhanced the differentiation of OPCs, which alleviated myelin loss and cognitive dysfunction (P<0.05). Conclusions: An age-related decline in oligodendrogenesis may compromise endogenous repair mechanisms, and CREB-activating therapies may rescue white matter after chronic cerebral hypoperfusion. Approaches that promote OPC function and repair may be useful for treating white matter rendered vulnerable by age in stroke or vascular dementia.