Background: Memory impairment is one of the most disturbing symptoms of Alzheimer’s disease (AD). Because ample research implicates the pro-inflammatory cytokine inerleukin-1 (IL-1) within the brain in various aspects of the pathophysiology of AD, and because in other medical conditions pathophysiological levels IL-1 produce detrimental effects on memory processes and neural plasticity, in the present application we propose to examine the causal relationship between this cytokine and AD-associated memory impairment. Working hypothesis and aims: Our main hypothesis is that IL-1 is causally linked to AD-associated memory impairment. A corollary hypothesis is that blockade of IL-1 signaling will attenuate AD-associated memory deficiencies. To test these hypotheses, we aim to examine the role of IL-1 in the memory disturbances that are displayed by mice with AD-like pathology, using pharmacological, neurosurgical and genetic methods of IL-1 signaling blockade. Methods: The role of IL-1 in memory disturbances will be tested in transgenic mice overexpressing mutated amyloid precursor protein (APP). These mice display AD-like pathology and were previously found to exhibit elevated brain IL-1 production as well as learning and memory deficits. IL-1 blockade in these mice will be achieved using 3 methods: 1) chronic administration of IL-1 receptor antagonist (IL-1ra) directly into the brain; 2) Transplantation into the hippocampus of neural/glial stem cells derived from neonatal transgenic mice overexpressing human IL-1ra. 3) Cross-breeding between the AD mice and transgenic mice with astrocyte-directed overexpression of brain IL-1ra. Expected results: Results from these studies are expected to demonstrate that blockade of IL-1 signaling, using either pharmacological treatment, stem cell technology or genetic interventions, can attenuate the memory disturbances associated with AD pathology Importance: Memory loss is one of the most disturbing symptoms of AD. We hope that our studies will implicate the brain IL-1 system as an important pathophysiological mediator of these symptoms. Such an understanding will have both theoretical importance, providing one of the first demonstrations of the relationships between brain inflammation and behavioral changes in AD, as well as clinical importance, providing insights for the development of novel preventive and therapeutic manipulations for AD-associated memory impairments, based on novel approaches to the contnueous inhibition of brain IL-1.