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

Kim, Bhumsoo; Figueroa‐Romero, Claudia; Pacut, Crystal; Backus, Carey; Feldman, Eva L.

doi:10.1074/jbc.m115.636852

Cited by 46 publications

(37 citation statements)

References 51 publications

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“…This pattern suggests that CSF autotaxin predicts AD neuropathology in a manner similar to dysmetabolism. Chronic application of insulin in vitro in human cortical stem cells appeared to induce insulin resistance and inhibit tau dephosphorylation [46]. Higher IR among cognitively normal, APOE4 late middle-aged participants also predicted higher total tau and phosphorylated tau [47], but not CSF amyloid.…”

Section: Discussionmentioning

confidence: 99%

Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes

McLimans

Willette

2017

JAD

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Background Obesity and insulin resistance are associated with neuropathology and cognitive decline in Alzheimer’s disease (AD). Objective Ecto-nucleotide pyrophosphatase/phosphodiesterase 2, also called autotaxin, is produced by beige adipose tissue, regulates metabolism, and is higher in AD prefrontal cortex (PFC). Autotaxin may be a novel biomarker of dysmetabolism and AD. Methods We studied Alzheimer’s Disease Neuroimaging Initiative participants who were cognitively normal (CN; n=86) or had mild cognitive impairment (MCI; n=135) or AD (n=66). Statistical analyses were conducted using SPSS software. Multinomial regression analyses tested if higher autotaxin was associated with higher relative risk for MCI or AD diagnosis, compared to the CN group. Linear mixed model analyses were used to regress autotaxin against MRI, FDG-PET, and cognitive outcomes. Spearman correlations were used to associate autotaxin and CSF biomarkers due to non-normality. FreeSurfer 4.3 derived mean cortical thickness in medial temporal lobe and prefrontal regions of interest. Results Autotaxin levels were significantly higher in MCI and AD. Each point increase in log-based autotaxin corresponded to a 3.5 to 5 times higher likelihood of having MCI and AD, respectively. Higher autotaxin in AD predicted hypometabolism in the medial temporal lobe [R2=0.343, p<0.001] and PFC [R2=0.294, p<0.001], and worse performance on executive function and memory factors. Autotaxin was associated with less cortical thickness in PFC areas like orbitofrontal cortex [R2=0.272, p<0.001], as well as levels of total tau, p-tau181, and total tau/Aβ1–42. Conclusions These results are comparable to previous reports using insulin resistance. CSF autotaxin may be a useful dysmetabolism biomarker for examining AD outcomes and risk.

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Section: Discussionmentioning

confidence: 99%

Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes

McLimans

Willette

2017

JAD

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“…In rodents, increased AMPKα1 Ser487 phosphorylation has been reported in brains and aortae from obese and diabetic mouse models, with concomitant increased basal phosphorylation of Akt [15,51], whereas increased AMPKα1/α2 Ser487/491 phosphorylation has been observed in muscles from glucose-infused rats [27]. In humans, infusion of glucose in healthy volunteers after sprinting increased phosphorylation of Ser487/491 in human vastus lateralis muscle, as assessed with an antibody that recognises both phosphorylated species [52].…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487

Heathcote

Mancini

Strembitska

et al. 2016

Biochemical Journal

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The key metabolic regulator, AMP-activated protein kinase (AMPK), is reported to be down-regulated in metabolic disorders, but the mechanisms are poorly characterised. Recent studies have identified phosphorylation of the AMPKα1/α2 catalytic subunit isoforms at Ser487/491, respectively, as an inhibitory regulation mechanism. Vascular endothelial growth factor (VEGF) stimulates AMPK and protein kinase B (Akt) in cultured human endothelial cells. As Akt has been demonstrated to be an AMPKα1 Ser487 kinase, the effect of VEGF on inhibitory AMPK phosphorylation in cultured primary human endothelial cells was examined. Stimulation of endothelial cells with VEGF rapidly increased AMPKα1 Ser487 phosphorylation in an Akt-independent manner, without altering AMPKα2 Ser491 phosphorylation. In contrast, VEGF-stimulated AMPKα1 Ser487 phosphorylation was sensitive to inhibitors of protein kinase C (PKC) and PKC activation using phorbol esters or overexpression of PKC-stimulated AMPKα1 Ser487 phosphorylation. Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues.

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“…Farris and colleagues have suggested that excessive insulin circulation during insulin resistance may lead to reduced degradation of Aβ [ 207 ]. Insulin resistance has also been found to alter tau dephosphorylation via inhibition of adenosine monophosphate-activated kinase [ 208 ], and tau hyperphosphorylation has been observed in the hippocampi of the fa/fa rat model of obesity, with the extent of phosphorylation being increased in aged rats [ 209 ]. Interestingly, the relationship between T2DM and AD does not appear to be one sided, with intrahippocampal injection of Aβ leading to decreased insulin sensitivity in male rats [ 210 ].…”

Section: The Metabolic Disorders and Admentioning

confidence: 99%

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

Newcombe

Camats-Perna

Silva

et al. 2018

J Neuroinflammation

437

302

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Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

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

Cited by 46 publications

References 51 publications

Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes

Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes

Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

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