Body temperature as a risk factor for Alzheimer’s disease

Holtzman, Arnold H.; Simon, Elliott W.

doi:10.1054/mehy.2000.1085

Cited by 21 publications

(10 citation statements)

References 24 publications

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“…In addition, many of the elderly humans have subnormal body temperatures (Fox et al, 1973;Keilson et al, 1985;Collins, 1992), and low body temperature has been proposed as a risk factor for AD (Holtzman and Simon, 2000). Our data support this hypothesis, with abnormal tau hyperphosphorylation as a molecular link.…”

Section: Discussionsupporting

confidence: 74%

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Planel¹,

Miyasaka²,

et al. 2004

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Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein.Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.

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Section: Discussionsupporting

confidence: 74%

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Planel¹,

Miyasaka²,

et al. 2004

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“…Several reports have suggested that anesthesia could increase the risk of AD (Bohnen et al, 1994a;Johansson and Skoog, 1996;Bone and Rosen, 2000), and hypothermia has also been proposed as a risk factor (Holtzman and Simon, 2000;Avila and Diaz-Nido, 2004). Here, we demonstrated that anesthesia-induced hypothermia led to AD-like tau hyperphosphorylation induced by inhibition of PP2A.…”

Section: Discussionsupporting

confidence: 51%

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

Planel¹,

Richter²,

Nolan³

et al. 2007

J. Neurosci.

342

327

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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.

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“…48, 49). Several reports have suggested that anesthesia could increase the risk of AD (5–7), (8), and hypothermia per se has also been proposed as a risk factor (50, 51). The combination of regional or general anesthetic exposure and cool operating room environment make most surgical patients mildly hypothermic.…”

Section: Discussionmentioning

confidence: 99%

Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia

Planel

Bretteville²,

Liu³

et al. 2009

FASEB j.

123

122

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Alzheimer's disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer's disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points-during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.

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Body temperature as a risk factor for Alzheimer’s disease

Cited by 21 publications

References 24 publications

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

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

Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia

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