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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    • "Several epidemiological studies have consistently demonstrated that midlife obesity is a risk factor for developing cognitive decline and dementia that is independent of other known vascular risk factors, such as hypertension and diabetes [7] [25] [26] [27]. Similarly, diets high in saturated fatty acids, a major cause of obesity, have been associated with increased risk of developing AD and exacerbation of AD pathology in several animal and human studies [28] [29] [30]. "
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    ABSTRACT: Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer's disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy.
    Full-text · Article · Nov 2015 · Biochimica et Biophysica Acta
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    • "Triple-transgenic mice (3xTg-AD) were produced in our laboratories and used as models of AD [37] [38]. As previously described, 3xTg-AD mice were studied at 3, 6, and 18 months of age to coincide with early, middle, and late plaque and tangle pathology, respectively [39] [40] [41]. "
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    ABSTRACT: The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (RAGE) and efflux (ABCB1-ABCG2-ABCG4-LRP-1) transporters and cholesterol transporter (ABCA1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H] cholesterol and [3H] Aβ 1-40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (RAGE) and decrease in efflux receptor (LRP-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, ABCG4 and ABCA1 are upregulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that ABCG4 and ABCA1 control the efflux of Aβ through the BBB by a direct (ABCG4) or indirect (ABCA1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant upregulation of both ABCG2 and ABCB1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.
    Full-text · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
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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.
    Full-text · Article · Jun 2014 · PLoS ONE
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