AMP-activated-protein-kinase (AMPK) is a key sensor and regulator of cellular and whole-body energy metabolism and plays a key role in regulation of lipid metabolism. Since lipid metabolism has been implicated in neuronal amyloid-beta (A beta) homeostasis and onset of Alzheimer's disease, we investigated the involvement of AMPK in neuronal lipid metabolism and A beta production. We observed in cultured rat cortical neurons that AD production was significantly reduced when the neurons were stimulated with AMPK activator, 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR), but increased when AMPK alpha 2 was knocked out, thus indicating the role of AMPK in amyloidogenesis. Although the detailed mechanisms by which AMPK regulates A beta generation is not well understood, AMPK-mediated alterations in cholesterol and sphingomyelin homeostasis and in turn the altered distribution of A beta precursor-protein (APP) in cholesterol and sphingomyelin rich membrane lipid rafts participate in A beta generation. Taken together, this is the first report on the role of AMPK in regulation of neuronal amyloidogenesis. (C) 2010 Published by Elsevier Inc.