Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis.
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 (Abeta) homeostasis and onset of Alzheimer's disease, we investigated the involvement of AMPK in neuronal lipid metabolism and Abeta production. We observed in cultured rat cortical neurons that Abeta production was significantly reduced when the neurons were stimulated with AMPK activator, 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR), but increased when AMPKalpha2 was knocked out, thus indicating the role of AMPK in amyloidogenesis. Although the detailed mechanisms by which AMPK regulates Abeta generation is not well understood, AMPK-mediated alterations in cholesterol and sphingomyelin homeostasis and in turn the altered distribution of Abeta precursor-protein (APP) in cholesterol and sphingomyelin rich membrane lipid rafts participate in Abeta generation. Taken together, this is the first report on the role of AMPK in regulation of neuronal amyloidogenesis.
Won
Je-Seong
JS
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, SC 29425, USA.
Im
Yeong-Bin
YB
Kim
Jinsu
J
Singh
Avtar K
AK
Singh
Inderjit
I
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation; D055786:Gene Knockout Techniques; D021962:Membrane Microdomains / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013109:Sphingomyelins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D013109:Sphingomyelins; D002784:Cholesterol; C543928:Prkaa2 protein, rat; D055372:AMP-Activated Protein Kinases