Physiological regulation of tau phosphorylation during hibernation

Abstract

The microtubule-associated protein tau is abnormally hyperphosphorylated in the brains of individuals with Alzheimer disease and other tauopathies, and is believed to play a critical role in the pathogenesis of these diseases. While the mechanisms leading to abnormal tau phosphorylation remain elusive, the recent demonstration of reversible tau phosphorylation during hibernation provides an ideal physiological model to study this critical process in vivo. In this study, arctic ground squirrels (AGS) during hibernation were used to study mechanisms related to tau hyperphosphorylation. Our data demonstrate that tau is hyperphosphorylated at all six sites (S199, T205, S214, S262, S396, and S404) examined in hibernating AGS. Interestingly, only three of these sites (S199, S262, and S404) are dephosphorylated in aroused animals, suggesting a reversible phosphorylation at selective sites. Summer-active AGS demonstrated the lowest tau phosphorylation at all these sites. To explore the mechanisms underlying increased tau phosphorylation during hibernation, the expression level and enzyme activity of various potential tau kinases and protein phosphatases were examined. The kinetic analysis of enzyme activity at different temperatures revealed differential changes in enzyme activity with temperature decline. Specifically, increased protein kinase A activity, decreased protein phosphatase 2A activity, as well as substantial contribution from glycogen synthase kinase-3b, likely play a key role in increased tau phosphorylation during hibernation in AGS.

Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a “master switch” regulating synaptic gain in neuronal networks

“…One cellular mechanism that contributes to the regulated suppression of metabolism and thermogenesis during hibernation is reversible phosphorylation of enzymes and other proteins, which limits rates of flux through metabolic pathways (14, 29, 80, 114, 189; (73, 186 -188), Arctic ground squirrels, and Black bear (186 -188), this mechanism of reversible protein phosphorylation also affects the microtubule-associated protein tau, a finding that was subsequently also replicated by another group (194). Thereby, a condition is generated that in the adult human brain is associated with aggregation of tau protein into paired helical filaments (PHFs), as observed in Alzheimer's disease and other tauopathies (20,63,64,82,83,111,169).…”

Neuroprotection: Lessons from hibernators

“…Suppression of cerebral metabolism leads to regional cooling in brains of patients with AD and cold-induced inhibition of serine-threonine protein phosphatase 2A may allow hyperphosphorylated tau to accumulate in AD (Planel et al, 2004). Hibernating animals are temperature compensated in a way that avoids cold-induced inhibition of the phosphatases necessary for reversal of tau phosphorylation (Su et al, 2008). In this way, these animals may be able to reap benefits from tau phosphorylation such as stabilization of the cytoskeleton, but avoid pathological events caused by failed phosphatase activity.…”

The Alzheimer's Disease-Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalance Limiting Successful Aging

“…Thus, it is not yet clear whether both diseases represent the endpoint of aged, exhausted, and dysfunctional cells having reached their maximal life expectancy or whether AD and T2D are the consequences of living in superabundance including excessive food supply, work demands, psychosocial stress, and an excessive sedentary life style [4][5][6][7][8][9]. Evidence for the latter is provided by the fact that high adiposity increases the risk of AD [10][11][12] and T2D [10,13] and implies that the progressive loss of energy balance is one underlying pathomechanism of both diseases.Interestingly, mammalian hibernators such as ground squirrels and hamsters demonstrate comparable and annual recurrent periods of obesity with concomitant insulin resistance and key features of AD such as tau phosphorylation [14,15]. These pathologies, however, are reversed by a time-dependent metabolic shift be- * Corresponding author: Angelika Bierhaus, PhD, Department of Medicine I, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.…”

“…Interestingly, mammalian hibernators such as ground squirrels and hamsters demonstrate comparable and annual recurrent periods of obesity with concomitant insulin resistance and key features of AD such as tau phosphorylation [14,15]. These pathologies, however, are reversed by a time-dependent metabolic shift be- * Corresponding author: Angelika Bierhaus, PhD, Department of Medicine I, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.…”

“…tween carbohydrate-and fat-based metabolism, a delicate balance of kinases and phosphatases and changes in gene expression [15][16][17]. While massive fat depots serve as the main source of metabolic fuel throughout the winter [18], phosphorylation of tau during obligate hibernation seems to be a reversible consequence of hypothermia [19,20].…”