Detrimental Effects of Diet-Induced Obesity on τ Pathology Are Independent of Insulin Resistance in τ Transgenic Mice

Leboucher, Antoine; Laurent, Cyril; Fernandez-Gomez, Francisco-José; Burnouf, Sylvie; Troquier, Laetitia; Eddarkaoui, Sabiha; Demeyer, Dominique; Caillierez, Raphaëlle; Zommer, Nadège; Vallez, Emmanuelle; Bantubungi, Kadiombo; Breton, Christophe; Pigny, Pascal; Buée‐Scherrer, Valérie; Staels, Bart; Hamdane, Malika; Tailleux, Anne; Buée, Luc; Blum, David

doi:10.2337/db12-0866

Cited by 90 publications

(76 citation statements)

References 38 publications

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“…Animal studies utilizing transgenic mouse models of AD have shown that a diet rich in saturated fat and cholesterol can increase AD-pathology hallmarks, such as amyloid levels, Tau phosphorylation, and behavioral deficits [28][29][30]. Furthermore, diet-induced obesity has been shown to potentiate Tau-pathology in mice [31,32], but it is not known whether these effects are exacerbated with aging, nor is it known whether the Tau phosphorylation cascade is involved in HFHCdiet induced cognitive impairment. Therefore, the aims of this study were to investigate the consequences of long-term consumption of a HFHC diet on cognitive performance, hippocampal morphology, and expression of phosphorylated Tau in young versus aged rats.…”

Section: Introductionmentioning

confidence: 99%

Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats

Ledreux

Wang

Schultzberg

et al. 2016

Behavioural Brain Research

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High fat diets have detrimental effects on cognitive performance, and can increase oxidative stress and inflammation in the brain. The aging brain provides a vulnerable environment to which a high fat diet could cause more damage. We investigated the effects of a high fat/high cholesterol (HFHC) diet on cognitive performance, neuroinflammation markers, and phosphorylated Tau (p-Tau) pathological markers in the hippocampus of Young (4-month old) versus Aged (14-month old) male rats. Young and Aged male Fisher 344 rats were fed a HFHC diet or a normal control diet for 6 months. All animals underwent cognitive testing for 12days in a water radial arm maze to assess spatial and working reference memory. Hippocampal tissue was analyzed by immunohistochemistry for structural changes and inflammation, and Western blot analysis. Young and Aged rats fed the HFHC diet exhibited worse performance on a spatial working memory task. They also exhibited significant reduction of NeuN and calbindin-D28k immunoreactivity as well as an increased activation of microglial cells in the hippocampal formation. Western blot analysis of the hippocampus showed higher levels of p-Tau S202/T205 and T231 in Aged HFHC rats, suggesting abnormal phosphorylation of Tau protein following the HFHC diet exposure. This work demonstrates HFHC diet-induced cognitive impairment with aging and a link between high fat diet consumption and pathological markers of Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats

Ledreux

Wang

Schultzberg

et al. 2016

Behavioural Brain Research

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“…According to the Rotterdam Study, levels of insulin and insulin resistance were associated with a higher risk of AD only within 3 years of baseline (Schrijvers et al 2010). Nevertheless, McNeilly et al (2012) showed that cognitive deficits observed in dietinduced-obese animals were not prevented by insulin sensitizers, while Leboucher et al (2013) have shown that obesity potentiate spatial learning deficits as well as hippocampal tau pathology in τ-transgenic mice, independently of insulin resistance state. Both of these studies have highlighted the relevance of insulin-independent mechanisms in the increased risk of dementia related to obesity.…”

Section: Introductionmentioning

confidence: 99%

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

2014

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Alzheimer's disease is the leading cause of dementia and the most prevalent neurodegenerative disease. It is an aging-related multi-factorial disorder and growing evidence support the contribution of metabolic factors to what was formerly thought to be a centrally mediated process. Obesity has already been recognized as an important player in the pathogenesis of this type of dementia, independently of insulin resistance or other vascular risk factors. Although the exact underlying mechanisms are still unknown, adipocyte dysfunction and concomitant alteration in adipocyte-derived protein secretion seem to be involved, since these adipocytokines can cross the blood-brain barrier and influence cognitive-related structures. Very few studies have assessed the role of adipocytokines dysfunction on cognitive impaired patients and yielded contradictory results. Interestingly, extensive research on the central effects of leptin in Alzheimer's diseasetransgenic mice has demonstrated its capacity to enhance synaptic plasticity and strength, as well as to prevent betaamyloid deposition and tau phosphorylation. In addition, adiponectin, the most abundant adipocytokine whose levels are inversely correlated to adiposity, has shown to be neuroprotective to hippocampal cells. Many other adipose-derived cytokines have mainly pro-inflammatory properties, being able to trigger and/or enhance central inflammatory cascades and also to influence the secretion of other adipocytokines involved in cognition. This paper pretends to review the existing evidence on the contribution of adipocytokines dysfunction to the increased risk of dementia associated with midlife obesity, unraveling its insulin-independent effects on cognition.

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“…Metabolic deregulations in animal models of tauopathies resemble those found in patients with Tau-related dementia. Indeed, decreased body weight has been described in a mouse model of Tau deposition such as THY-22 [148] or Tg4510 [149, 150], sometimes despite increased feeding behavior [151]. Additionally, genetic deletion of Tau resulted in increased body weight [152].…”

Section: Brain Insulin Resistance In Ad and Tauopathies: Cause Or Conmentioning

confidence: 99%

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

et al. 2018

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Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood. Insulin is a hormone involved in the control of energy homeostasis both peripherally and centrally, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that insulin resistance can exacerbate Tau lesions, mainly by disrupting the balance between Tau kinases and phosphatases. On the other hand, the emerging literature indicates that Tau protein can also modulate insulin signalling in the brain, thus creating a detrimental vicious circle. The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies. Considering that insulin signalling is prone to be pharmacologically targeted at multiple levels, it constitutes an appealing approach to improve both insulin brain sensitivity and mitigate brain pathology with expected positive outcome in terms of cognition.

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Detrimental Effects of Diet-Induced Obesity on τ Pathology Are Independent of Insulin Resistance in τ Transgenic Mice

Cited by 90 publications

References 38 publications

Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats

Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

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