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

Article (PDF Available)inNeurobiology of aging 31(9):1516-31 · November 2008with182 Reads
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.
    • "However, the relationship between imaging biomarkers and early midlife pathogenic changes leading to AD, such as obesity, has remained elusive . Since obesity-driven inflammation and metabolic impairment have been identified as important mechanisms accelerating AD pathogenesis and functional impairment [9][10][11][12][13], they may represent potential early-stage imaging markers of cognitive decline and AD risk. Neuroinflammation has been identified as a contributor to both the initiation and progression of AD. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Obesity has been identified as a risk factor for cognitive decline and Alzheimer’s disease (AD). The aim of this study was to investigate the effect of obesity on neuroinflammation and cerebral glucose metabolism using PET in a mouse model of β-amyloidosis and determine the relationship between these PET imaging biomarkers, pathogenic changes, and functional outcomes. Methods Three-month-old C57BL/J6 mice were fed either a standard (control group) or high-fat diet (obese group) for 3 months and intracerebroventricularly infused with vehicle or human beta amyloid 1-42 (Aβ42). We assessed obesity-induced abnormalities in peripheral metabolic indices including adiposity, fasting glucose, and glucose tolerance. Brain glucose metabolism was assessed by 18F-FDG PET, and glial activation was assessed using the translocator protein (TSPO) ligand 11C-PBR-28. TSPO expression was confirmed by immunohistochemistry of brain sections obtained from scanned mice. The association between inflammatory state and 11C-PBR-28 PET signals was characterized by examination of the cytokine expression profile in both the serum and hippocampus by antibody array. Learning and memory performance was assessed in the object recognition task, and anxiety-related behavior was assessed in the elevated plus maze. ResultsObesity combined with Aβ infusion promoted neuroinflammation and cerebral hypermetabolism, and these signals were significant predictors of learning and memory performance in the object recognition task. In vivo TSPO signals were associated with inflammatory markers including CXCL1, CXCL2, CXCL12, CCL3, CCL5, TIMP-1, G-CSF, sICAM-1, and IL-1ra. Conclusions In vivo cerebral metabolism and TSPO signals indicate that obesity can accelerate amyloid-induced inflammation and associated cognitive decline.
    Full-text · Article · Aug 2016
    • "Thus, surprisingly , the significant increase in body weight in the HF groups of mice does not affect speed of movement (Leamy et al., 2009; Zhang and Gershenfeld, 2003), although there is a trend for this group to move the slowest of all, compared to the other diets. While the finding that diets high in fat content have a negative influence on cognition (both in social recognition and water maze) in both the WT and Tg animals was not unexpected (Julien et al., 2010; Kesby et al., 2015; Levin-Allerhand et al., 2002; Maesako et al., 2012; Petrov et al., 2015 ), one should keep in mind that previous studies have indicated that the high-fat induced memory impairments are not necessarily directly related to the Aβ load in Tg AD model mice (El Akoum et al., 2011; Knight et al., 2014 ). Our data, similarly, do not show a HF diet increase in Aβ load in the hippocampus, while we do see cognitive deficits . "
    [Show abstract] [Hide abstract] ABSTRACT: Clinical and epidemiological evidence suggests that lifestyle factors, including nutrition, may influence the chances of developing of Alzheimer's disease (AD), and also likely affect the aging process. Whereas it is clear that high-fat diets are increasing both body weight and the risk of developing Alzheimer's disease, to date, there have been very few studies comparing diets high with different sources of calories (i.e., high fat versus high protein versus high carbohydrates) to determine whether dietary composition has importance beyond the known effect of high caloric intake to increase body weight, AD pathology and cognitive deficits. In the current study we examined the effects that different diets high in carbohydrate, protein or fat content, but similar in caloric value, have on the development of cognitive impairment and brain pathology in wild-type and Tg AD model mice. The results demonstrate that long term feeding with balanced diets similar in caloric content but with significant changes in the source of calories, all negatively influence cognition compared to the control diet, and that this effect is more pronounced in Tg animals with AD pathology.
    Full-text · Article · May 2016
    • "Therefore, the accumulation of A and tau may further exacerbate the adverse effects on synaptic and cognitive function and consequently induce cell death.Table 1. Diabetes promotes amyloid pathology (Abbreviations: intraperitoneal i.p.; intracerebroventricular i.c.v.). (Arancio et al., 2004; Devi et al., 2012; Ho et al., 2004; Jolivalt et al., 2010; Julien et al., 2010; Kim et al., 2013b; Lane et al., 2010; Leuner et al., 2012; Li et al., 2007; Liu et al., 2009a; Macauley et al., 2015; Takeda et al., 2010; Wang et al., 2014) Impaired insulin signaling induced an overactivation of GSK-3 kinase, and the downregulation of O- GlcNAcylation, which resulted in tau and neurofilament hyperphosphorylation, and neurofibrillary degeneration. Kim et al., 2009 Single STZ injection (i.p) of 55 mg/kg in Ntg mice STZ-induced hyperglycemia altered the Akt/GSK- 3/PP2A cascade, and leads to the development of abnormal tau phosphorylate forms. "
    [Show abstract] [Hide abstract] ABSTRACT: Despite intensive research efforts over the past few decades, the mechanisms underlying the etiology of sporadic Alzheimer’s disease (AD) remain unknown. This fact is of major concern because the number of patients affected by this medical condition is increasing exponentially and the existing treatments are only palliative in nature and offer no disease modifying affects. Interestingly, recent epidemiological studies indicate that diabetes significantly increases the risk of developing AD, suggesting that diabetes may play a causative role in the development of AD pathogenesis. Therefore, elucidating the molecular interactions between diabetes and AD is of critical significance because it might offer a novel approach to identifying mechanisms that may modulate the onset and progression of sporadic AD cases. This review highlights the involvement of several novels pathological molecular mechanisms induced by diabetes that increase AD pathogenesis. Furthermore, we discuss novel findings in animal model and clinical studies involving the use of anti-diabetic compounds as promising therapeutics for AD.
    Full-text · Article · Mar 2016
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