Hypothermia and Alzheimer's Disease ...

Current Alzheimer Research, 2010, 7, 000-000

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Hypothermia and Alzheimer's Disease Neuropathogenic Pathways R.A. Whittington1, M.-A. Papon2, F. Chouinard-Decorte2 and E. Planel2,* 1

Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, 622 West 168th Street PH 5, New York, NY 10032, USA; 2Département de Psychiatrie et Neurosciences, Centre Hospitalier de l'Université Laval, 2705 Boulevard Laurier, Québec, G1V 4G2, Canada Abstract: Alzheimer’s disease (AD) remains a major health problem, and accounts for 50 to 60% of all cases of dementia. The two histopathological hallmarks of AD are senile plaques, composed of the -amyloid peptide (A), and intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. Only a small proportion of AD is due to mutations in the genome of patients, the large majority of cases being of late onset and sporadic in origin. The relative contribution of genetics and environment to the sporadic cases is unclear, but they are accepted to be of multifactorial origin. This means that genetic and environmental factors can interact together to induce or accelerate the disease. Among environmental factors, studies suggest that hypothermia may contribute to the development and exacerbation AD. Here, we review the preclinical data involving hypothermia with tau and A, as well as clinical evidence implicating hypothermia in the development of AD.

Keywords: Alzheimer’s dementia, tau, beta-amyloid, phosphorylation, hypothermia, PP2A, phosphatases. INTRODUCTION Alzheimer’s disease (AD) is a neurodegenerative disorder leading to amnesia, cognitive impairment and dementia. As of 2006, there are approximately 27 million individuals afflicted with AD, and it is estimated that without a significant treatment breakthrough this number will approximately quadruple by the middle of this century [1]. The histopathological features of AD have been documented for close to a century since their initial description by Alois Alzheimer [2]. They include brain atrophy due to massive neurodegeneration, extracellular accumulations of -amyloid peptides (A) as senile plaques [3], and intraneuronal neurofibrillary tangles (NFTs), composed of abnormally hyperphosphorylated tau protein assembled into paired helical filaments (PHF) [4]. Only a small proportion of AD is due to autosomal dominant genetic variants, and occurs before 65 years of age (familial AD). The large majority cases (over 99%) are late onset and sporadic in origin [5]. The cause of sporadic AD is unknown, but it is likely to be multifactorial, with external factors interacting with biological or genetic susceptibility to accelerate the manifestation of the disease. Among external factors, several studies suggest that hypothermia may contribute to the development and exacerbation AD. Normal body temperature in humans is between 36.5 and 37.5˚C, and hypothermia is defined as subnormal body temperature. For the purpose of this review, hypothermia will be defined as a body temperature of 36˚C or lower. In this article, we assess the clinical and biochemical evidence implicating hypothermia as a risk factor for the development of AD. *Address correspondence to this author at the CHUL, RC-9800, 2705 Boulevard Laurier, Québec, G1V 4G2, Canada; Tel: 418-656-4141 (Ext: 47805); Fax: 418-654-2753; E-mail: [email protected] 1567-2050/10 $55.00+.00

HYPOTHERMIA AS A RISK FACTOR FOR ALZHEIMER'S DISEASE Clinically, hypothermia has been classified in four different magnitudes: mild, moderate, deep or severe, and profound. The definition of the temperature range differs according to the author, with mild from 32-34˚C to 35-36˚C, moderate from 26-28˚C to 31-33˚C, deep from 10-20˚C to 25-27°C, and profound from 4-14˚C to 9-19˚C [6]. In the following section, we examine a selection of potential causes of hypothermia in humans and their relations with AD. Aging Elderly humans regulate core temperature less efficiently than younger adults in hot or cold environments [7], and many of them have subnormal body temperatures [8-10]. They are prone to hypothermia for a variety of reasons including decreased basal metabolism, less intense shivering, decreased muscle mass that generate fewer calories, loss of body fat, decreased sensitivity to cold and changes in temperatures, as well as abnormal vasoconstrictor responses to cold [11]. The possibility of hypothermia is also increased secondary to debilitating conditions or medications that make them unable to react to changes in temperature. Secondary hypothermia is the most common feature upon admission to the hospital for the elderly [12], this age group being particularly vulnerable to hypothermia since thermoregulatory mechanisms are impaired in both normal aging and in chronic disease states associated with advanced age [11]. Studies in older individuals have found an incidence of hypothermia of up to 10% in those living at home, and as high as 34% in those hospitalized [11]. Aging is the most important risk fac-tor for Alzheimer's disease [13, 14], and an increased incidence of hypothermia during aging may be a risk factor for AD [15, 16].

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Diabetes Mellitus As we have seen above, aging is considered to be the most important risk factor for late-onset sporadic AD. Other common syndromes in the elderly include diabetes mellitus (DM), impaired glucose tolerance (IGT), insulin resistance, as well as the relative decrease of pancreas endocrine activity and insulin secretion associated with aging [17]. Around 40% of individuals over 65 years old and 50% of individuals older than 80 have IGT or DM, and nearly half of the elderly diabetics are undiagnosed [17]. Insulin signaling seems to be involved in the modulation of lifespan and brain aging [18], and there is increasing evidence supporting a link between AD and insulin dysfunction [19]. For example, compared to age-matched controls, AD brains show abnormalities in insulin and insulin receptor levels [20, 21], and these abnormalities might play a role in the reduction of regional glucose metabolism that have been widely reported in AD [22]. Population-based and cohort studies have also detected higher AD incidences rates in DM patients [23-25]. Hypothermia is a common outcome in human diabetes [26, 27], and hypothermia may be a contributing factor in the higher incidence rates of AD in DM patients. Anesthesia Postoperative cognitive dysfunction, confusion, and delirium are common after general anesthesia in the elderly, with symptoms persisting for months or years in some patients [28-32]. Although the risk of developing symptoms increases with age, even middle-aged patients are likely to have postoperative cognitive dysfunction for months after surgery [33]. Some reports suggest that AD patients may be particularly at risk of deterioration after anesthesia [34, 35]. Several investigators have thus examined whether general anesthesia is associated with AD. Some studies find no association [36-43], while others suggest that exposure to anesthetics may increase the risk of AD [35, 44, 45]. Thus, anesthesia might be associated with long-term cognitive disorder and the acceleration of senile dementia [46, 47]. Recent preclinical studies (reviewed below) suggest that inhalation anesthetics may in fact contribute to the onset and pathogenesis of AD, both directly and indirectly through hypothermia, but the clinical evidence remains circumstantial (reviewed in [48, 49]). During surgery, the combination of regional or general anesthetic exposure and cool operating room environment make most surgical patients mildly hypothermic [50]. While hypothermia may be beneficial for specific, critically ill patients particularly during surgery requiring neuroprotection, perioperative hypothermia following anesthesia is clearly harmful for most patients as it has been associated with serious physiologic perturbations including systemic and pulmonary vasoconstriction, myocardial ischemia, impaired coagulation, increased wound infection rates, the potentiation of anesthetic drug effects, and a decreased ventilatory response to oxygen [51, 52]. Consequently, multiple methods have been developed for the management of core temperature [53]. However, most of the studies examining the relationship between anesthesia and the subsequent development of AD did not document thermal management methods and body temperatures of patients during and after sur-

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gery. Careful statistical evaluation of temperature data from existing or future studies should be performed in the multivariate analysis, in order to reach a more definitive conclusion regarding the link between anesthesia, temperature, and the subsequent risk of the development and progression of AD as well as to identify any possible preventative measures. Other Causes of Hypothermia In humans, the causes of hypothermia have been classified as primary and secondary. In primary or accidental hypothermia, the thermoregulatory mechanisms are functioning correctly, but are overwhelmed by low temperature, such as immersion in cold water. Secondary hypothermia is due to the failure of proper thermoregulation associated with a number of causes such as underlying cardiovascular, neurological or endocrine disease, mental illness, severe infections, drug abuse, alcoholism, and malnutrition [54]. Many drugs such as anesthetics (as seen above), hypnotics, anxiolytics, and antidepressants can affect body temperature regulation [54]. Specific processes associated with secondary hypothermia include myocardial infarction, stroke, paraplegia, dementia, parkinsonism, diabetes mellitus, hypothyroidism, hypopituitarism, bronchopneumonia, and medications [54]. For example, low basal temperature is a symptom of hypothyroidism, which has been associated with cognitive impairment and Alzheimer's disease (reviewed in [55]). All these sources of secondary hypothermia might enhance the progression of Alzheimer's disease. HYPOTHERMIA AND APP METABOLISM One of the hallmarks of Alzheimer's disease is extracellular accumulation of -amyloid peptides (A) as senile plaques. A peptides are the cleavage product of the amyloid precursor protein (APP), a secreted glycoprotein whose function is not well understood. APP has a transmembrane domain, an N-terminal extracellular domain, and a C-terminal intracellular domain. APP can be cleaved either by nonamyloidogenic -secretase, or amyloidogenic -secretase pathways. -secretase cleavage generates a soluble Nterminal APP fragment (sAPP) that is secreted from the cell, and a 83-residue C-terminal fragment (CTF or C83) that remains membrane-associated. This cleavage occurs within the A peptide sequence and prevents the generation of A. -secretase cleavage of APP occurs within the extracellular domain and generates two fragments: a large, soluble N-terminal fragment (sAPP) that is secreted from the cell, and a transmembrane, 99-residue membrane-associated C-terminal fragment (CTF or C99) containing the whole A peptide that remains associated with the cell. CTF is then cleaved in the middle of the transmembrane domain and results in a series of A peptides where major variants contain either 40 or 42-residues (A40 and A42). Contrary to A40, the A42 is prone to aggregation and is considered the neurotoxic species [3]. In AD, APP metabolism is affected, with changes in A and C-terminal fragments levels [56]. We investigated whether there was any change in APP metabolism during hypothermia following 1h of choral hydrate anesthesia. While there was robust tau hyperphos-

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phorylation, there was no alteration in APP levels or APP Cterminal fragments. Similarly, the levels of endogenous A140 and A1-42 did not change during anesthesia [57]. This is in contrast with the studies of Bianchi et al. and Perrucho et al., who found increased amyloidopathy in mutant APP mice (Tg2576) following anesthesia by either isoflurane or halothane [58, 59]. However, both studies controlled the temperature of the mice to prevent hypothermia, demonstrating that the effect of anesthesia on amyloidogenesis was due to the anesthetics per se. Thus, the evidence so far suggests that acute hypothermia has no effect on the amyloidogenic pathway. However, further studies with chronic or repeated hypothermia are warranted to definitely conclude that low temperatures do not affect APP metabolism and A pathology.

pS214 epitopes, in addition to the previous epitopes. Extracellular ghost tangles are most prominently stained with AT8 (pS199/pS202/pT205), AT100 (pT212/pS214), and PHF-1 (pS396/pS404) antibodies, which also stain intraneuronal tangles [78, 79]. The distribution pattern of NFT in the brain of AD patients is highly hierarchical and is divided in 6 stages [80, 81]. The gradual invasion of the brain by NFT changes has also been confirmed biochemically by its typical pattern on SDS-PAGE, and has been classified in 10 stages according to the affected region [82]. Understanding the factors that naturally affect tau phosphorylation is thus important as tau pathology shows a strong relationship to dementia in AD, memory loss in normal aging as well as mild cognitive impairment [83-86].

HYPOTHERMIA AND TAU

Tau Phosphorylation During Hypothermia

Tau in the Normal and Alzheimer's Brain

Recent in vitro and in vivo studies have demonstrated that hypothermia is a potent initiator of tau hyperphosphorylation. Indeed, neuronal cultures exposed to temperatures lower that 37˚C demonstrate that hypothermia produces tau hyperphosphorylation in vitro. Moreover, there are numerous conditions including cold-water swimming, hibernation, starvation, insulin, deoxyglucose, diabetes, or anesthesia that induce hypothermia, and subsequently result in abnormal tau hyperphosphorylation in vivo. In this section, we review the evidence provided from these studies and examine the potential neuropathological consequences of hypothermia-induced hyperphosphorylation on tau function and pathology.

Tau is an axonal microtubule-associated protein (MAP) that is abundant in the central nervous system. The microtubule-binding domain of tau mediates its most characterized biological functions: to stabilize microtubules (MT) and promote their polymerization [60-62]. In the human brain, tau proteins constitute a family of six isoforms, ranging from 352 to 441 amino acids, and each isoform is a product of alternative splicing of a single gene located on chromosome 17 (17q21-22) [63]. The amino-terminal region is characterized by the presence or absence of one or two inserts, interacts with the plasma membrane, and is essential for determining axonal diameter [64]. The carboxy-terminal region is characterized by the presence of 3 or 4 repeats that mediate the microtubule (MT) binding properties of tau as well as promote MT stabilization and polymerization [65-67]. The longest tau isoform bears 45 Ser, 35 Thr and 5 Tyr putative phosphorylation sites, and at least 30 Ser/Thr phosphorylation sites have been described, many of them being proline-directed [4]. Tau binding to MT and its ability to promote MT assembly is negatively regulated by phosphorylation at multiple sites in, and around, the MT binding domain [4, 68]. Indeed, when phosphorylated, several sites, such as Thr231, Ser396 or Ser404, but especially Ser262 in the MT binding domain, dramatically reduce the affinity of tau for microtubules and its capacity to stabilize them [6972]. Furthermore, tau phosphorylation is regulated by numerous kin-ases and phosphatases; among them, the glycogen synthase kin-ase-3 beta (GSK-3) and protein phosphatase 2A (PP2A) are considered to be the major tau kinase and phosphatase, respectively, regulating tau hyperphosphorylation in vivo [73, 74]. Intracellular aggregates of abnormally hyperphosphorylated tau are present in a group of neurodegenerative diseases called tauopathies [4]. Tau hyperphosphorylation can induce aggregation in vitro [75, 76], and is thought to induce NFT formation in the brain [77]. In Alzheimer's disease, the accumulation of NFT in neurons is preceded by appearance of abnormally hyperphosphorylated tau. In fact, the phosphorylation of tau seems to vary according to the stage of tangle formation. For example, tau in pre-tangles is mostly phosphorylated at TG3 (Thr231), Thr153, and serines 199, 202, 262, and 409. Intraneuronal tangles are mostly phosphorylated at pT175/181, 12E8 (pS262/pS356), pS422, pS46, and

In Vitro Hypothermia Metabolically active mouse brain slices display normal levels of tau phosphorylation when incubated at 37˚C. However, as soon as they are incubated at room temperature (23˚C), tau hyperphosphorylation at the AT8 epitope (pS199/ pS202/pT205) occurs rapidly, reaching 200% of control levels after 5 min, 500% after 30 min, and more than 1000% 1h later [87]. Further characterization of this phenomenon showed that tau hyperphosphorylation at pS199, AT8, pT231, and pS422 occurred as soon as the temperature decreased from 37˚C, reaching a plateau between 20 and 30˚C. At 15˚C, tau phosphorylation was still higher than at 37˚C, but when all enzymatic activities were stopped at 1˚C (on ice), tau was no longer hyperphosphorylated [87]. The hyperphosphorylation of tau has also been observed in neuroblastoma cells (SH-SY5Y, N2A) and primary neuronal cultures incubated at 30˚C (unpublished results). These results clearly demonstrated that low temperatures can induce tau hyperphosphorylation directly in vitro. Cold-Water Swimming We have also observed tau hyperphosphorylation following hypothermia in vivo. For example, cold-water swimming has been reported to lead to rapid tau hyperphosphorylation at pS199, AT8, pS262 and Thr231/Ser235 epitopes in the rodent brain [88, 89]. Although this has been suggested to be stress-related [88], this effect is probably due to hypothermia and not to the effect of stress hormones, as Korneyev et al. demonstrated persistent tau hyperphosphorylation following cold- water swimming after removal of adrenal glands or treatment with cortisone [90]. Indeed, cold-water swimming


induces low body temperatures (16.3±1.0˚C just after treatment, and 25.1±1.6˚C after 30 min. in mice), and swimming in warm water does not induce tau hyperphosphorylation [87]. Thus, a decrease in body temperature resulting from cold water immersion also leads to tau hyperphosphorylation. Hibernation Hibernation is a unique physiological state of inactivity, characterized by low metabolic rate, and low body temperature during bouts of prolonged torpor, periodically interrupted by brief periods of arousal and rewarming [91]. Hibernating animals conserve energy, especially during winter when food is short, and the animal's slowed metabolic rate leads to a reduction in body temperature. Hibernation has been shown to induce tau hyperphosphorylation in obligate hibernators such as European ground squirrels [92], Arctic ground squirrels [93], and facultative hibernators such as Syrian hamsters [94]. In European ground squirrels, Arendt et al. [92] observed that tau phosphorylation at the AT8 epitope was highest during long torpor (body temperature ~8.2˚C), high during short torpor (~9.8˚C) or short arousal (~30.9˚C), and low during long arousal (~34.5˚C) or in nonhibernating normothermic squirrels (~36.5˚C). Hence, although hypothermia might not be the only cause of tau phosphorylation during hibernation, it is likely to be a major contributor to the extent of the hyperphosphorylation. Altered Glucose Metabolism We previously reported that reductions in glucose metabolism, either by starvation, insulin overdose or deoxyglucose injection, result in tau hyperphosphorylation through hypothermia. Starvation decreases the amount of circulating glucose and insulin, and lowers glucose utilization [95, 96], resulting in hypothermia and AD-like tau hyperphosphorylation (pS199, AT8, AT100, pT231, pS262, pS396, pS404, pS413, pS422) in mice [87, 97, 98]. In these experiments, starvation was induced by the total deprivation of food, and not solely with caloric restriction. Furthermore, overdoses of insulin depress glucose metabolism through acute hypoglycemia [99], and also result in hypothermia-induced tau hyperphosphorylation (pS199, AT8, AT100, pT231, pS262, pS396, pS404, pS422) [87]. 2-deoxy-D-glucose is a glucose analog that inhibits glycolysis and oxidative metabolism of glucose, while producing hyperglycemia with little effect on serum insulin levels [100]. Interestingly, deoxyglucose injections have been observed to result in hypothermia and tau hyperphosphorylation (pS199, AT8, pT231, pS262, pS396, pS404, pS422) in mice [87]. Thus, decreases in basal glucose metabolism that result in hypothermia ultimately lead to tau hyperphosphorylation. Diabetes Mellitus Hypothermia is a common outcome in both human diabetes [26, 27] and experimental diabetic animals [101, 102]. In experimental diabetes, the occurrence of hypothermia has generally been associated with a multitude of thermogenic abnormalities such as the reduction in non-shivering thermogenesis [103], lack of shivering activity [101], and the inability to utilize carbohydrates for heat production [104]. Induction of either type 1 or type 2 diabetes in rodents has

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been reported to result in tau hyperphosphorylation [105109], and tau phosphorylation seems to be elevated in the brains of diabetic patients [110]. To investigate the mechanism of tau hyperphosphorylation during type 1 diabetes, we injected mice with streptozotocin, which induces experimental diabetes by specifically destroying the pancreatic islets of Langerhans [111]. We demonstrated that diabetes induced by streptozotocin results in tau hyperphosphorylation at pS199, AT8, AT180 (pS231), pS262, pS356, PHF-1 (pS396/404), pS400, and pS422 epitopes through two distinct mechanisms: one consequent to hypothermia and induced by impaired glucose/energy metabolism and the other a temperature-independent process that is inherent to insulin deficiency and induced by the inhibition of the activities of serine/threonine phosphatases [107]. Hypothermia is thus a very common occurrence during diabetes and should be controlled for when analyzing tau phosphorylation in experimental models of this disease. Anesthesia All general anesthetics markedly impair normal autonomic thermoregulatory control. Inhalation and intravenous anesthetics, as well as opioids substantially decrease the thresholds for vasoconstriction and shivering, thus resulting in hypothermia [53]. Clinically hypothermia during anesthesia is a very common clinical occurrence secondary to the inhibition of thermoregulation by anesthetics and the patient’s exposure to the cold operating room environment [51]. Moreover, the elderly, who are themselves at risk for the development of AD, are particularly susceptible to intraoperative hypothermia as they have less subcutaneous tissue, which renders thermoregulation by means of vasoconstriction and shivering less effective than younger adults [112]. We previously observed that anesthesia induced by chloral hydrate, sodium pentobarbital or isoflurane induced a robust hyperphosphorylation of tau at pS199, AT8, TG3 (pT231), MC6 (pS235), pS262, PHF-1 and pS422 epitopes, as demonstrated by Western blotting, ELISA and immunohistochemical analysis. The restoration of normothermia in the mice completely returned phosphorylation to normal levels, demonstrating that tau hyperphosphorylation is not mediated by the anesthetics per se, but is the consequence of hypothermia [57]. Tau phosphorylation is exquisitely sensitive to temperature, increasing by 80% per degree Celsius drop under 37˚C in mice [57]. Recently, other investigators have also reported increased tau phosphorylation following hypothermia induced by pentobarbital [113], ketamine, or urethane [114]. Anesthesia-induced hypothermia is also used as an easy and convenient model of in vivo tau hyperphosphorylation [115-117]. Ether anesthesia, which leads to hypothermia [118], has also been reported to induce tau hyperphosphorylation in mice, although the authors did not report the temperature of the animals [119]. Hence, general anesthetics are powerful thermoregulatory depressants leading to tau hyperphosphorylation. Mechanism We have shown that the effect of hypothermia on tau phosphorylation can be largely attributed to direct inhibition of serine/threonine protein phosphatase 2A (PP2A) [57, 87,


107]. Other investigators have demonstrated inhibition of PP2A during hibernation [93, 120, 121]. We have demonstrated that low temperatures lead to direct, exponential inhibition of brain phosphatases, while tau kinases activities decreased linearly with temperature. Moreover, in brain slices, hypothermia did not induce the activation of four major tau kinases (GSK-3b, MAPK, JNK and cdk5) [87]. Tau can be dephosphorylated by protein phosphatase 1 (PP1), PP2A and protein phosphatase 2B (PP2B) in vitro, but PP2A possesses a much stronger capacity to dephosphorylate tau [122, 123]. Inhibitors studies in brain slices have demonstrated that PP2A is likely to be the main regulator of tau phosphorylation in vivo, while PP1 and PP2B are minimally involved [124, 125]. Moreover, PP2A expression is about 15 times more elevated than PP1 in the brain [126], and there is strong evidence supporting the role of PP2A as the major tau phosphatase in vivo [74]. In addition, there is extensive literature related to the inhibition of PP2A in cell cultures, neuronal cultures and in vivo, which demonstrates that the inhibition of PP2A always results in multi-epitope hyperphosphorylation of tau [74]. Thus, tau hyperphosphorylation during hypothermia is mainly due to the direct inhibition of PP2A, as no single kinase is responsible for the hyperphosphorylation of tau at multiple epitopes observed under these conditions. However, it is important to understand that this statement does not imply that kinases are not involved in tau phosphorylation during hypothermia. On the contrary, in vivo tau hyperphosphorylation can be induced by basal kinases activities, even though they are inhibited or not activated, simply by a shift in phosphorylation equilibrium as a result of phosphatase inhibition [57]. In other words, inhibiting PP2A is the functional equivalent of activating all the tau kinases together because PP2A dephosphorylates all the known tau epitopes while each kinase is specific for only a set of given sites [127]. Indeed, even when GSK-3 is inhibited as a consequence to hypothermia, it is still participating to the phosphorylation of tau, as we previously demonstrated with lithium, a GSK-3 inhibitor, in mice rendered hypothermic by starvation [98]. Thus, hyperphosphorylation during hypothermia is due to direct inhibition of PP2A activity towards tau. Implications These findings have important implications for the study of tau in laboratory animals, as there are numerous events that can induce hypothermia and can be confounding factors when analyzing tau phosphorylation. For example, lipopolysaccharide-induced inflammation was reported to enhance tau phosphorylation and pathology in a transgenic model of AD [128], but LPS is known to induce hypothermia [129, 130]. Heat shock results in tau dephosphorylation followed by hyperphosphorylation in rats [131], but heat shock is usually followed by hypothermia [132]. Likewise, restraint stress induces hypothermia [133], and tau hyperphosphorylation [134], as does MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin causing Parkinson's disease symptoms) injections [133, 135, 136]. These examples are not given to imply that hypothermia is the main cause of tau hyperphosphorylation in each case, but to illustrate the fact that hypothermia is a very common phenomenon that should be always controlled for. The mouse, with its high body sur-


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face area-to-mass ratio, is particularly prone to body temperature imbalances [7]. Some transgenic mice, like those carrying A Precursor Protein (APP) mutations, seem especially vulnerable to hypothermia [137, 138]. Thus, when analyzing tau phosphorylation, the animal's body temperature should always be reported to eliminate the possibility that changes in tau phosphorylation are not artifactually introduced into the experiment by hypothermia. Likewise, precautions should be taken to minimize the exposure of cell and neuronal cultures to temperatures that could result in hypothermic conditions. Consequences on Tau Function and Pathology The most well characterized biological functions of tau are to stabilize microtubules (MT) and promote their polymerization, and these are negatively regulated by hyperphosphorylation. Hyperphosphorylation has been proposed to impair tau function by dissociating it from MT, thereby destabilizing the MT and disrupting MT-dependent axonal transport [77, 139-141]. Using anesthesia to induce low body temperatures, we examined how hypothermia-induced tau hyperphosphorylation influences in vivo tau function, by means of several MT assays: endogenous MT binding assay, exogenous MT binding assay, MT assembly assay, and electron-micro-scope examination of MT structure. Our results in C57BL/6J mice demonstrated that hyperphosphorylation impaired tau’s ability to bind and polymerize MT, but did not result in its detachment from MT. Hyperphosphorylation of tau in transgenic mice expressing all six isoforms of human tau (hTau mice [142]) led to specific dissociation of 3repeat (3R) tau from the MT in aged mice. However, neither wild-type nor hTau mice displayed a breakdown of the MT network [117]. Thus, hypothermia-induced tau hyperphosphorylation reduces the capacity of free tau to bind to MT, but tau already bound to MT is difficult to detach. Moreover, the fraction of tau remaining bound to the MT seems to be enough to maintain their integrity. Of note, in these studies, the mice were examined after only few hours of hypothermia, and it is indeed possible that more chronic hypothermia, even to a mild degree, could lead to more pronounced effects on tau function and MT network integrity. We also investigated the short and long-term effect of anesthesia-induced hypothermia on tau pathology in a mouse model of tauopathy (line JNPL3) expressing the TauP301L mutation that causes frontotemporal lobe dementia and with relevance to the neurofibrillary pathology observed in AD [143, 144]. We observed that hypothermia led to increased tau phosphorylation and accumulation of aggregated tau species, and this was accompanied by detachment of tau from MT. Overall, our results suggest that hypothermia induced by anesthesia leads to the acceleration of tau pathology in vivo. CONCLUSION Holtzman and Simon were the first to propose the hypothesis of body temperature as a risk factor for Alzheimer's disease [15]. Among the anecdotes and evidence they presented to support their hypothesis, include the tendency for the elderly to display cold intolerance (e.g., sweaters in summertime, hothouse conditions in winter), as well as their


own study demonstrating that patients with Down Syndrome -who develop full AD pathology- have a significant decrease in body temperature across the range of ages studied. They argued that in the context of low temperature over long periods, even a small difference is enough to add to the progression of the disease for those at risk, and that the disease itself may lead to a lowered body temperature that, in turn, accelerates the pathology. There is currently no direct evidence that hypothermia has a negative influence on the clinical course and outcome of patients with AD. However, as previously mentioned, in clinical studies, hypothermia has not been included as a variable in the statistical analysis. As we have seen in this review, all the evidence is preclinical and indirect, and derives from the demonstration that hypothermia can enhance tau phosphorylation and pathology in rodents. Nevertheless, since tau pathology shows a strong relationship to dementia in AD as well as to memory loss in normal aging and mild cognitive impairment, we propose hypothermia as a risk factor for AD. We also hypothesize that the development of AD pathology in brain regions known to be involved in thermoregulation, such as the hypothalamus, might lead to a vicious cycle promoting more pathology. Therefore, further clinical studies in humans examining the influence of hypothermia on the subsequent development and progression of AD are warranted. REFERENCES [1] [2]

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