High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model

Faculty of Pharmacy, Laval University, Quebec, QC, Canada.
Neurobiology of aging (Impact Factor: 4.85). 11/2008; 31(9):1516-31. DOI: 10.1016/j.neurobiolaging.2008.08.022
Source: PubMed

ABSTRACT To investigate potential dietary risk factors of Alzheimer's disease (AD), triple transgenic (3xTg-AD) mice were exposed from 4 to 13 months of age to diets with a low n-3:n-6 polyunsaturated fatty acid (PUFA) ratio incorporated in either low-fat (5% w/w) or high-fat (35% w/w) formulas and compared with a control diet. The n-3:n-6 PUFA ratio was decreased independently of the dietary treatments in the frontal cortex of 3xTg-AD mice compared to non-transgenic littermates. Consumption of a high-fat diet with a low n-3:n-6 PUFA ratio increased amyloid-beta (Abeta) 40 and 42 concentrations in detergent-insoluble extracts of parieto-temporal cortex homogenates from 3xTg-AD mice. Low n-3:n-6 PUFA intake ratio increased insoluble tau regardless of total fat consumption, whereas high-fat diet incorporating a low n-3:n-6 PUFA ratio also increased soluble tau compared to controls. Moreover, the high-fat diet decreased cortical levels of the postsynaptic marker drebrin, while leaving presynaptic proteins synaptophysin, SNAP-25 and syntaxin 3 unchanged. Overall, these results suggest that high-fat consumption combined with low n-3 PUFA intake promote AD-like neuropathology.

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Available from: Frédéric Calon, Jul 28, 2015
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    • "D'autres de nos travaux ont montré un effet antiinflammatoire puissant du DHA [43]. À l'inverse, une diète forte en gras totaux mais faibles en oméga 3 conduit à une augmentation importante de la neuropathologie Alzheimer [46]. Dans le domaine de la maladie de Parkinson, des effets moteurs favorables [66] et neuroprotecteurs [45] [67] des acides gras oméga 3 ont également été rapportés. "
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    ABSTRACT: Numerous studies in animals have confirmed that the lipid content of the brain mirrors the dietary intake. Since most brain lipids are neuroactive, it then appears possible to modulate brain function through the choice of lipids in the diet. Epidemiological investigations and preclinical studies in animal models suggest that polyunsaturated fatty acids omega 3 can be used to prevent Alzheimer's disease. However, specific expression of the ɛ4 apolipoprotein isoform appears to neutralize cerebral benefits of omega 3 fatty acids, possibly by reducing its transport though the blood-brain barrier. At the opposite, excessive consumption of total fats exerts a deleterious effect on the neuropathological markers of Alzheimer's disease. Overall, the accumulated scientific evidence suggests that a judicious selection of dietary fatty acids, in terms of both quality and quantity, deserves further study in the prevention of brain diseases. Given the current lack of effective pharmaceutical treatment, the development of an anti-Alzheimer nutraceutical approach seems achievable.
    Cahiers de Nutrition et de Diététique 06/2014; DOI:10.1016/j.cnd.2014.03.003
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    • "However, levels of both phosphorylated and total Tau were not affected in the brain of non-transgenic animals treated with HFD, although Tau mRNA levels were significantly increased (Moroz et al., 2008). Similarly, levels of total soluble and insoluble Tau, but not phospho-Tau were increased in HFD fed 3xTg-AD transgenic mice, suggesting that effects of HFD are modest on Tau phosphorylation (Julien et al., 2010). On the other hand, a recent study has demonstrated that HFD leads to Tau phosphorylation in a model of Tauopathy treated with HFD, in a manner independent of insulin resistance, suggesting that, other obesity-related factors, might contribute to Tau pathology (Leboucher et al., 2012). "
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    ABSTRACT: The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.
    Frontiers in Cellular Neuroscience 02/2014; 8:22. DOI:10.3389/fncel.2014.00022 · 4.18 Impact Factor
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    • "Interestingly, the HF diet alters tau isoform expression and increased phosphorylation of tau at Ser202 site in female mice regardless of genotype (Hiltunen et al., 2012). Another study has shown that HF diets increase the Aβ burden and the level of tau hyperphosphorylation; furthermore, this administration also induces the decreased cortical levels of the postsynaptic marker drebrin (Julien et al., 2010). In vitro studies have also reported these effects, analyzing the intracellular pathways and cell signaling mechanisms in more detail. "
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    ABSTRACT: Abstract Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves many underlying pathological processes. Recently, it has been demonstrated that AD also includes impairments of insulin signaling in the brain. Type 2 diabetes is a risk factor for AD, and AD and diabetes share a number of pathologies. The classical hallmarks of AD are senile plaques and neurofibrillary tangles, which consist of amyloid-β and hyperphosphorylated tau. Based on the two hallmarks, transgenic animal models of AD have been developed, which express mutant human genes of amyloid precursor protein, presenilin-1/2, and tau. It is likely that these mouse models are too limited in their pathology. In this work, we describe mouse models that model diabetes and show insulin signaling impairment as well as neurodegenerative pathologies that are similar to those seen in the brains of AD patients. The combination of traditional AD mouse models with induced insulin impairments in the brain may be a more complete model of AD. Interestingly, AD mouse models treated with drugs that have been developed to cure type 2 diabetes have shown impressive outcomes. Based on these findings, several ongoing clinical trials are testing long lasting insulin analogues or GLP-1 mimetics in patients with AD.
    Reviews in the neurosciences 12/2013; 24(6):607-615. DOI:10.1515/revneuro-2013-0034 · 3.31 Impact Factor
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