Roles of AMP-activated Protein Kinase in Alzheimer’s Disease

Abstract

AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis and a central player in glucose and lipid metabolism, is potentially implicated in the pathogenesis of Alzheimer's disease (AD). AMPK activity decreases in AD brain, indicating decreased mitochondrial biogenesis and function. Emerging evidence demonstrates that AMPK activation is a potential target for improving perturbed brain energy metabolism that is involved in the pathogenesis of AD. The roles of AMPK in the pathogenesis of AD include β-amyloid protein (Aβ) generation and tau phosphorylation. In particular, AMPK may regulate Aβ generation through modulating neuronal cholesterol and sphingomyelin levels and through regulating APP distribution in the lipid rafts. AMPK is activated by phosphorylation of Thr-172 by LKB1 complex in response to increase in the AMP/ATP ratio and by calmodulin-dependent protein kinase kinase-beta in response to elevated Ca(2+) levels, which contributes to regulating Aβ generation. AMPK is a physiological tau kinase and can increase the phosphorylation of tau at Ser-262. AMPK can also directly phosphorylate tau at Thr-231 and Ser-396/404. Furthermore, AMPK activation decreases mTOR signaling activity to facilitate autophagy and promotes lysosomal degradation of Aβ. However, AMPK activation has non-neuroprotective property and may lead to detrimental outcomes, including Aβ generation and tau phosphorylation. Therefore, it is still unclear whether AMPK could serve a potential therapeutic target for AD, and hence, further studies will be needed to clarify the role of AMPK in AD.

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

“…26 There are contradictory reports of AMPK activation in AD; however, new evidence suggests gender-specific effects of AMPK activation. 27 In addition, low levels of AMPK activation have been associated with improved cognition, whereas a higher degree of activation was linked to elevated catecholamine levels, induced neuronal apoptosis, and impaired cognition.…”

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

“…C57BL6 (B6) mice, a commonly used model to study diet-induced obesity (20,21,22,23), were also from Jackson Laboratory. Obesity was induced in B6 mice by placing them on a high fat diet (HFD) consisting of 54% kcal from fat (D05090701; Research Diets Inc., New Brunswick, NJ;) at 4 weeks of age until 24 weeks of age, whereas control mice were fed a standard diet consisting of 10% kcal from fat (D12450B; Research Diets Inc.) ( Table 1).…”

“…One theory suggests perturbed brain energy metabolism as the cause of pathogenic development of AD and cognitive impairment in general (20). Disruption in energy metabolism increases IR, affects glucose metabolism, and causes mitochondrial dysfunction, all of which are risk factors for AD (21). AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme and a key player in regulating energy metabolism (22).…”

“…Furthermore, increased AMPK activation is observed in tangle-and pretangle-bearing neurons in AD brain (29). This activation of AMPK requires phosphorylation at threonine 172 (AMPK ), a residue in its ␣-subunit, by upstream kinases such as liver kinase B1 (LKB1) or Ca 2ϩ /calmodulin-dependent protein kinase kinase ␤ (21,30). AMPK is also phosphorylated at serine 485 (AMPK ) by Akt, which reduces Thr-172 phosphorylation and inhibits AMPK activation (31,32); however, the direct contribution of Ser-485 on AMPK activation has not been extensively studied.…”

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

“…Thus, Aß accumulation leads to an increased calcium flux through NMDAR and thus triggers both the CAMKK and the ERK1/2 mediated activation of AMPK [40]. While Ca 2+ concentration and Aß accumulation are interdependent, the latter is prevented by the action of AMPK [41] and by the deacetylase SIRT1 [42]. SIRT1 also inhibits the formation of tau aggregates [43].…”