Role of GSK‐3β in Alzheimer's disease pathology

167

140

The microtubule-associated protein Tau is a major component of the neurofibrillary tangles that serve as a neuropathological hallmark of Alzheimer's disease. Tau is a substrate for protein phosphorylation at multiple sites and occurs in tangles in a hyperphosphorylated state. However, the physiological functions of Tau phosphorylation or how it may contribute mechanistically to Alzheimer's pathophysiology are not completely understood. Here, we examined the function of human Tau phosphorylation at three sites, Ser199, Ser202, and Thr205, which together comprise the AT8 sites that mark abnormal phosphorylation in Alzheimer's disease. Overexpression of wild-type Tau or mutated forms in which these sites had been changed to either unphosphorylatable alanines or phosphomimetic aspartates inhibited mitochondrial movement in the neurite processes of PC12 cells as well as the axons of mouse brain cortical neurons. However, the greatest effects on mitochondrial translocation were induced by phosphomimetic mutations. These mutations also caused expansion of the space between microtubules in cultured cells when membrane tension was reduced by disrupting actin filaments. Thus, Tau phosphorylation at the AT8 sites may have meaningful effects on mitochondrial movement, likely by controlling microtubule spacing. Hyperphosphorylation of the AT8 sites may contribute to axonal degeneration by disrupting mitochondrial transport in Alzheimer's disease.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease

Shahpasand

Uemura²,

Saito³

et al. 2012

167

140

“…However, we could not rule out anesthesia-specific activation of tau kinases that would contribute significantly to the observed tau hyperphosphorylation. Among the kinases able to phosphorylate tau in vitro, GSK-3␤, cdk5, MAPK/ERK (extracellular signal-regulated kinase), and JNK are considered to be major physiological and pathological tau kinases (Maccioni et al, 2001;Planel et al, 2002;Zhu et al, 2002). CaMKII is also thought to have a major role in regulating the phosphorylation of tau at epitopes that modulates the binding of tau to microtubules (Litersky et al, 1996;Sironi et al, 1998).…”

Section: Anesthesia-induced Tau Hyperphosphorylation Was Not Attributmentioning

confidence: 99%

Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia

Planel¹,

Richter²,

Nolan³

et al. 2007

339

327

Postoperative cognitive dysfunction, confusion, and delirium are common after general anesthesia in the elderly, with symptoms persisting for months or years in some patients. Even middle-aged patients are likely to have postoperative cognitive dysfunction for months after surgery, and Alzheimer's disease (AD) patients appear to be particularly at risk of deterioration after anesthesia. Several investigators have thus examined whether general anesthesia is associated with AD, with some studies suggesting that exposure to anesthetics may increase the risk of AD. However, little is known on the biochemical consequences of anesthesia on pathogenic pathways in vivo. Here, we investigated the effect of anesthesia on tau phosphorylation and amyloid precursor protein (APP) metabolism in mouse brain. We found that, regardless of the anesthetic used, anesthesia induced rapid and massive hyperphosphorylation of tau, rapid and prolonged hypothermia, inhibition of Ser/Thr PP2A (protein phosphatase 2A), but no changes in APP metabolism or A␤ (␤-amyloid peptide) accumulation. Reestablishing normothermia during anesthesia completely rescued tau phosphorylation to normal levels. Our results indicate that changes in tau phosphorylation were not a result of anesthesia per se, but a consequence of anesthesia-induced hypothermia, which led to inhibition of phosphatase activity and subsequent hyperphosphorylation of tau. These findings call for careful monitoring of core temperature during anesthesia in laboratory animals to avoid artifactual elevation of protein phosphorylation. Furthermore, a thorough examination of the effect of anesthesia-induced hypothermia on the risk and progression of AD is warranted.

“…We next investigated the molecular mechanisms underlying these two events. Among the kinases able to phosphorylate tau in vitro, GSK-3␤, cdk5, MAPK/ERK (extracellular signal-regulated kinase), and JNK are considered to be major physiological and pathological tau kinases (Maccioni et al, 2001;Planel et al, 2002;Zhu et al, 2002). CaMKII is also thought to have a major role in regulating the phosphorylation of tau at epitopes that modulate the binding of tau to microtubules (Litersky et al, 1996;Sironi et al, 1998).…”

Section: Stz-induced Tau Hyperphosphorylation Is Not Attributable To mentioning

confidence: 99%

Insulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms

Planel¹,

Tatebayashi²,

Miyasaka³

et al. 2007

225

172

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of the disease. The large majority of AD cases is late onset and sporadic in origin, with aging as the most important risk factor. Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are other common syndromes in the elderly also strongly age dependent, and there is evidence supporting a link between insulin dysfunction and AD. To investigate the possibility that insulin dysfunction might promote tau pathology, we induced insulin deficiency and caused DM in mice with streptozotocin (STZ). A mild hyperphosphorylation of tau could be detected 10, 20, and 30 d after STZ injection, and a massive hyperphosphorylation of tau was observed after 40 d. The robust hyperphosphorylation of tau was localized in the axons and neuropil, and prevented tau binding to microtubules. Neither mild nor massive tau phosphorylation induced tau aggregation. Body temperature of the STZ-treated mice did not differ from control animals during 30 d, but dropped significantly thereafter. No change in ␤-amyloid (A␤) precursor protein (APP), APP C-terminal fragments, or A␤ levels were observed in STZ-treated mice; however, cellular protein phosphatase 2A activity was significantly decreased. Together, these data indicate that insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity.