AMP-activated protein kinase (AMPK) is an energy sensing metabolic switch in mammalian cells. Here, we report our novel finding that AMPK is lost in all immune cells of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of Central Nervous System (CNS). AMPK alpha 1 is predominantly expressed in T cells and antigen presenting cells (APCs), which are primarily involved in EAE disease progression. AMPK is lost at protein level in spleen macrophages, total T cells and their subsets (CD4, CD8 and regulatory T cells) isolated from EAE afflicted animals compared to control, without affecting its mRNA levels suggesting that the loss of AMPK protein is the result of posttranscriptional modification. To examine its pathological relevance in inflammatory disease, EAE was induced in wild type (+/+) and AMPK alpha 1 ull mice (-/-) using MOG(35-55) peptide. AMPK alpha 1(-/-) mice exhibited severe EAE disease with profound infiltration of mononuclear cells compared to wild type mice however, AMPK alpha 2 is not involved in enhancing the severity of the disease. Spleen cells isolated from AMPK alpha 1(-/-) immunized mice exhibited a significant induction in the production of IFN gamma. Our study identifies AMPK as a down regulated target during disease in all immune cells and possibly restoring AMPK may serve as a novel therapeutic target in autoimmune diseases like multiple sclerosis (MS). (C) 2009 Elsevier Inc. All rights reserved.