Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis

► AMPK regulates lipid metabolism (cholesterol and sphingomyelin) in response to cellular and body energy states. ► Inactivation of AMPK may elevate neuronal cholesterol and sphingomyelin levels and increased APP distribution in lipid rafts. ► The increased APP distribution in lipid rafts causes an increased APP processing by β-secretase (BACE) and Aβ generation. ► Therefore, activation of neuronal AMPK may be beneficial for controlling Aβ generation. 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-β (Aβ) homeostasis and onset of Alzheimer’s disease, we investigated the involvement of AMPK in neuronal lipid metabolism and Aβ production. We observed in cultured rat cortical neurons that Aβ production was significantly reduced when the neurons were stimulated with AMPK activator, 5-aminoimidazole-4-carboxamide-1- d-ribofuranoside (AICAR), but increased when AMPKα2 was knocked out, thus indicating the role of AMPK in amyloidogenesis. Although the detailed mechanisms by which AMPK regulates Aβ generation is not well understood, AMPK-mediated alterations in cholesterol and sphingomyelin homeostasis and in turn the altered distribution of Aβ precursor-protein (APP) in cholesterol and sphingomyelin rich membrane lipid rafts participate in Aβ generation. Taken together, this is the first report on the role of AMPK in regulation of neuronal amyloidogenesis.