LAUSR

ABSTRACT Chronic cerebral hypoperfusion (CCH), a leading cause of various cerebrovascular diseases, leads to cognitive dysfunction due to neuron loss and impaired neurogenesis. Liver X receptors (LXRs), including LXR&agr; and LXR&bgr; isoforms, are crucial for cholesterol metabolism, synaptic plasticity as well as neurogenesis. However, it is not clear the potential roles of LXRs in the pathogenesis of cognitive impairment induced by CCH. In this study, we demonstrated that LXR&bgr; expression decreased in hippocampus of CCH mice. GW3965, a synthetic dual agonist for both LXR&agr; and LXR&bgr;, ameliorated impairment of learning and memory in CCH mice by promoting neuronal survival and neural stem cells (NSCs) proliferation in dentate gyrus (DG) of CCH mice. The proliferative effects of GW3965 were further confirmed in cultured neural progenitor cells (NPCs) and showed in a concentration‐dependent manner. Moreover, GW3965 phosphorylated protein kinase B (Akt) at Ser473 in a time‐ and concentration‐dependent manner in NPCs. Furthermore, both LY294002, an inhibitor for phosphoinositide‐3‐kinase (PI3K), and short hairpin RNAs for LXR&bgr; knockdown, abrogated GW3965‐induced Akt phosphorylation, and therefore abolished GW3965‐mediated proliferation‐promoting of NPCs. All the data suggested that GW3965 ameliorated impaired cognitive functions in CCH by promoting NSC proliferation through PI3K/Akt pathway followed LXR&bgr; activation. This study correlates a deficit of LXR&bgr; in cognitive dysfunction in CCH with impaired neurogenesis in hippocampus, and LXRs may serve as a potential therapeutic target for chronic cerebral ischemia. HIGHLIGHTSActivation of LXRs by GW3965 ameliorates CCH‐induced cognitive deficit in mice.GW3965 treatment promotes the neuronal survival and NSC proliferation in Hipp of CCH mice.GW3965 treatment promotes NSC proliferation through PI3K/Akt pathway followed LXR&bgr; activation.