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

Abstract

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-Dribofuranoside (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.

Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt-mediated Increase in AMPKSer-485 Phosphorylation

“…It is reported that AMPK activation reduces amyloid ␤ production in rat cortical neurons (24) and that leptin and resveratrol reduce amyloid ␤ levels and Tau phosphorylation through AMPK activation (25)(26)(27). In contrast, AMPK can directly phosphorylate Tau, and amyloid ␤-induced increases in Tau phosphorylation require AMPK-activated Ca 2ϩ /calmodulin-dependent protein kinase kinase ␤ (28).…”

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

“…Vingtdeux et al [130] demonstrated that there was abnormal accumulation of activated AMPK in tangle-and pretangle-bearing neurons in AD. AMPK signaling can regulate tau protein phosphorylation and amyloidogenesis [131]. AMPK is also a potent activator of autophagic degradation, which seems to be suppressed in AD.…”

AMPK in the central nervous system: physiological roles and pathological implications

“…74,78 In the same way, many studies have described the divergent evidence about the involvement of AMPK in brain tumors and ischemic stroke. The presence of contradictory results indicates that further investigations are needed to better dissect the molecular mechanisms linking AMPK activity and the development of CNS diseases.…”

“…On the contrary, Aβ peptide levels are increased when AMPKα2 is knocked out, thus indicating the crucial involvement of AMPK in amyloidogenesis. 74 AMPK controls Aβ generation through the modulation of neuronal cholesterol and sphingomyelin levels, which regulate APP distribution in lipid rafts. 67 In addition, leptin-induced AMPK activation is associated with a reduction in Tau phosphorylation.…”