P2‐316: Disturbance in AMP‐activated protein kinase (AMPK) signaling pathway in Alzheimer's disease

AMP-activated protein kinase (AMPK) has been suggested as a molecular hub for cellular metabolic control and accumulating evidence supports a disturbance in AMPK activity and its regulatory pathways in many different types of diseases including neurological diseases. In fact, AMPK is highly expressed in the brain with a predominant neuronal localization and shown to be activated by resveratrol as well as metablic stress. Since metabolic stress is one of the key pathological alterations in Alzheimer disease (AD) and the pathogenic mechanism is unclear, we hypothesizes that decreased activity of AMPK is keen to the mechanism of metabolic defects found in AD. To this end, in this study, we analyzed the expression of AMPK in AD brains and investigated the pathophysiological role of AMPK in AD. The expression pattern of AMPK in AD was analyzed by a series of molecular techniques and included the AD model systems that were investigated for the role of AMPK in the pathogenesis of AD. Counter to our hypothesis, the level of active AMPK was dramatically increased in AD brains and mainly localized in the vulnerable neurons containing neurofibrillary tangles (NFT). The pathological implications of this finding will be discussed based on the results from the AD model systems. Our results clearly demonstrate that AMPK is significantly activated in the vulnerable neurons in AD. While the pathological consequence(s) of such AMPK activation is yet to be determined, it is likely that the activation of AMPK in AD might not be neuroprotective as shown in previous studies. Indeed, the activation of AMPK has been linked to neurodegeneration and aberrant processing of amyloid-β precursor proteins, suggesting that the higher activity of AMPK might be harmful to neurons and this potential mechanism will be discussed.