The current study aimed to investigate the behavioral, biochemical and histological changes in lipopolysaccharide (LPS)-induced AD, to study effect of estrogen in AD clarifying the possible involved underlying mechanisms and its modulation by progesterone. LPS-induced AD produced deterioration of cognitive and motor functions which was further aggravated by OVX. Estrogen improved the cognitive and motor dysfunction partly through anti-inflammatory, anti-oxidant, anti-apoptotic and anti Aβ effects mediated partly through ER-α which was potentiated by co-administration of progesterone suggesting either a direct neuroprotective role of progesterone or an indirect action through potentiation of estrogen neuroprotective mechanisms.