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

Faculty of Pharmacy, Laval University, Quebec, QC, Canada.
Neurobiology of aging (Impact Factor: 5.01). 11/2008; 31(9):1516-31. DOI: 10.1016/j.neurobiolaging.2008.08.022
Source: PubMed


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, Oct 05, 2015
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    • "It is possible therefore that an increase in tau phosphorylation may play a role in the memory impairment observed in female high-fat fed 3xTgAD offspring. In support, high-fat diets during adulthood increase tau pathology in 3xTgAD mice [16] and also in other AD and tau-expressing mouse models [57]–[59]. These effects of a high-fat diet on tau might be due to a change in free fatty acids (FFA) profile, as saturated FFA, which are associated with obesity and high-fat diets, can increase tau phosphorylation in cortical neurones in vitro [60]. "
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    ABSTRACT: Alzheimer's disease (AD) is not normally diagnosed until later in life, although evidence suggests that the disease starts at a much earlier age. Risk factors for AD, such as diabetes, hypertension and obesity, are known to have their affects during mid-life, though events very early in life, including maternal over-nutrition, can predispose offspring to develop these conditions. This study tested whether over-nutrition during pregnancy and lactation affected the development of AD in offspring, using a transgenic AD mouse model. Female triple-transgenic AD dam mice (3xTgAD) were exposed to a high-fat (60% energy from fat) or control diet during pregnancy and lactation. After weaning (at 3 weeks of age), female offspring were placed on a control diet and monitored up until 12 months of age during which time behavioural tests were performed. A transient increase in body weight was observed in 4-week-old offspring 3xTgAD mice from dams fed a high-fat diet. However, by 5 weeks of age the body weight of 3xTgAD mice from the maternal high-fat fed group was no different when compared to control-fed mice. A maternal high-fat diet led to a significant impairment in memory in 2- and 12-month-old 3xTgAD offspring mice when compared to offspring from control fed dams. These effects of a maternal high-fat diet on memory were accompanied by a significant increase (50%) in the number of tau positive neurones in the hippocampus. These data demonstrate that a high-fat diet during pregnancy and lactation increases memory impairments in female 3xTgAD mice and suggest that early life events during development might influence the onset and progression of AD later in life.
    PLoS ONE 06/2014; 9(6):e99226. DOI:10.1371/journal.pone.0099226 · 3.23 Impact Factor
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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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    • "Disease neuropathology and/or behavioral deficits are enhanced in mouse models of AD that are maintained on a high-fat diet (without high levels of cholesterol) (Herculano et al., 2013; Ho et al., 2004; Julien et al., 2010; Maesako et al., 2012a; Pedrini et al., 2009; Phivilay et al., 2009). There are several well-characterized mouse models of AD, most with mutations in amyloid precursor protein (APP) and/or presenilin 1/2 (PS1/2) that present with Aβ plaques only. "
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    ABSTRACT: Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Diets high in fat also increase disease neuropathology and/or cognitive deficits in AD mouse models. However, the effect of a high-fat diet on both the neuropathology and memory impairments in the triple-transgenic mouse model of AD (3xTgAD) is unknown. Therefore, groups of 2-month-old male 3xTgAD and control (non-Tg) mice were maintained on a high-fat or control diet and memory was assessed at the age of 3-4, 7-8, 11-12, and 15-16 months using a series of behavioral tests. A comparable increase in body weight was observed in non-Tg and 3xTgAD mice after high-fat feeding at all ages tested but a significantly greater increase in epididymal adipose tissue was observed in 3xTgAD mice at the age of 7-8, 11-12, and 15-16 months. A high-fat diet caused memory impairments in non-Tg control mice as early as the age of 3-4 months. In 3xTgAD mice, high-fat consumption led to a reduction in the age of onset and an increase in the extent of memory impairments. Some of these effects of high-fat diet on cognition in non-Tg and 3xTgAD mice were transient, and the age at which cognitive impairment was detected depended on the behavioral test. The effect of high-fat diet on memory in the 3xTgAD mice was independent of changes in AD neuropathology as no significant differences in (plaques, oligomers) or tau neuropathology were observed. An acute increase in microglial activation was seen in high-fat fed 3xTgAD mice at the age of 3-4 months but in non-Tg control mice microglial activation was not observed until the age of 15-16 months. These data indicate therefore that a high-fat diet has rapid and long-lasting negative effects on memory in both control and AD mice that are associated with neuroinflammation, but independent of changes in beta amyloid and tau neuropathology in the AD mice.
    Neurobiology of aging 02/2014; 35(8). DOI:10.1016/j.neurobiolaging.2014.02.010 · 5.01 Impact Factor
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