Activation of the 5′-AMP-Activated Protein Kinase in the Cerebral Cortex of Young Senescence-Accelerated P8 Mice and Association with GSK3β- and PP2A-Dependent Inhibition of p-tau396 Expression

Moon

Molecular Medicine Reports

et al. 2017

Self Cite

Senescence-accelerated mouse prone 8 (SAMP8), a non‑transgenic animal model used for researching sporadic Alzheimer's disease (AD), presents AD pathologies and overall dysregulation in brain energy metabolism, which is one of the early pathogenic characteristics of AD. In the present study, the authors examined chronological changes in the expression patterns of phosphorylated tau and of proteins related to energy metabolism to evaluate the association of tau phosphorylation and metabolism, using young‑ (2‑months‑old), middle‑ (5‑months‑old) and old‑aged (10‑months‑old) SAMP8. The levels of phosphorylated 5'‑AMP activated protein kinase at Thr172 (p‑AMPK) and phosphorylated glycogen synthase kinase 3β (p‑GSK3βS9) in the cortex of SAMP8 at 2 months were significantly higher than those in senescence‑accelerated mouse resistant 1 (SAMR1). The differences were not detected at 5 and 10 months of age, which were concurrent with the changes in levels of phosphorylated tau at Ser396 (p‑tauS396), but not with p‑tauS262. The level of p‑tauS262 was considerably higher in the cortex of middle‑aged SAMP8 when compared with that of SAMR1 and sustained in old‑aged SAMP8, but not in the young cortex. The levels of cortical sirtuin1 (Sirt1) and insulin receptor substrate 1 (IRS‑1) expression of young SAMP8 were significantly lower, when compared with those in SAMR1. However, in the hippocampus of SAMP8, the patterns of chronological changes and levels of p‑tau, p‑AMPK, Sirt1 and IRS‑1 relative to SAMR1 were different from those in the cortex. Taken together, the results suggested that regulation of tau phosphorylation via the AMPK‑GSK3β pathway concurrent with dysregulation of energy metabolism may precede the pathological tau hyperphosphorylation in the cortex of SAMP8, and that the regulation of AMPK‑GSK3β‑mediated tau phosphorylation may be dependent on phosphor‑epitope in tau or the region of brain.

Section: Discussionmentioning

confidence: 62%

Section: Chronological Changes In the Expression Of Phosphorylated Tamentioning

confidence: 89%

Chronological changes in the expression of phosphorylated tau and 5-AMP-activated protein kinase in the brain of senescence-accelerated P8 mice

Moon

Molecular Medicine Reports

et al. 2017

Self Cite

BioMed Research International

“…Phosphorylation at this site is mediated by different kinases, but it is reported that GSK3β is the major tau kinase [103]. In addition, the level of hyperphosphorylation is regulated by the balance between phosphorylation by the different kinases and activity of dephosphorylating enzymes phosphatases mainly protein phosphatases 2A (PP2A) [104].…”

Section: Ampk and Tauopathymentioning

confidence: 99%

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

Assefa

Tafere

Wondafrash

et al. 2020

Alzheimer’s disease is a multifactorial neurodegenerative disease characterized by progressive cognitive dysfunction. It is the most common form of dementia. The pathologic hallmarks of the disease include extracellular amyloid plaque, intracellular neurofibrillary tangles, and oxidative stress, to mention some of them. Despite remarkable progress in the understanding of the pathogenesis of the disease, drugs for cure or disease-modifying therapy remain somewhere in the distance. From recent time, the signaling molecule AMPK is gaining enormous attention in the AD drug research. AMPK is a master regulator of cellular energy metabolism, and recent pieces of evidence show that perturbation of its function is highly ascribed in the pathology of AD. Several drugs are known to activate AMPK, but their effect in AD remains to be controversial. In this review, the current shreds of evidence on the effect of AMPK activators in Aβ accumulation, tau aggregation, and oxidative stress are addressed. Positive and negative effects are reported with regard to Aβ and tauopathy but only positive in oxidative stress. We also tried to dissect the molecular interplays where the bewildering effects arise from.

“…Activated AMPK is abnormally accumulated in tangle-and pre-tangle-bearing neurons in AD patients and other tauopathies (Vingtdeux et al 2011). AMPK activation has been shown to influence tau phosphorylation at Ser 262 , Ser 356 and Ser 396 (Yoshida and Goedert 2012;Thornton et al 2011;Lee et al 2013;Kim et al 2015) and Ab production (Vingtdeux et al 2010;Won et al 2010;Chen et al 2009), although the results were conflicting.…”

Section: Introductionmentioning

confidence: 97%

Glucose regulates amyloid β production via AMPK

et al. 2015

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Accumulation of Aβ peptides in the brain has been suggested as the cause of AD (amyloid cascade hypothesis); however, the mechanism for the abnormal accumulation of Aβ in the brains of AD patients remains unclear. A plethora of evidence has emerged to support a link between metabolic disorders and AD. This study was designed to examine the relationship between energy status and Aβ production. Neuro 2a neuroblastoma cells overexpressing human amyloid precursor protein 695 (APP cells) were cultured in media containing different concentrations of glucose and agonist or antagonist of AMP-activated-protein-kinase (AMPK), a metabolic master sensor. The results showed that concentrations of glucose in the culture media were negatively associated with the activation statuses of AMPK in APP cells, but positively correlated with the levels of secreted Aβ. Modulating AMPK activities affected the production of Aβ. If APP cells were cultured in high glucose medium (i.e., AMPK was inactive), stimulation of AMPK activity decreased the production levels of Aβ. On the contrary, if APP cells were incubated in medium containing no glucose (i.e., AMPK was activated), inhibition of AMPK activity largely increased Aβ production. As AMPK activation is a common defect in metabolic abnormalities, our study supports the premise that metabolic disorders may aggravate AD pathogenesis.