Abstract
ObjectiveAlzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD.MethodsFrom 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate); (3) high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate); or (4) high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat). At age 18 wks, mice were sacrificed, and brains studied for (a) wet weight; (b) solubilizable Aβ content by ELISA; (c) amyloid plaque burden; (d) stereologic analysis of selected hippocampal subregions.ResultsAnimals receiving a high fat diet showed increased brain levels of solubilizable Aβ, although we detected no effect on plaque burden. Unexpectedly, brains of mice fed a high protein/low carbohydrate diet were 5% lower in weight than brains from all other mice. In an effort to identify regions that might link loss of brain mass to cognitive function, we studied neuronal density and volume in hippocampal subregions. Neuronal density and volume in the hippocampal CA3 region of TgCRND8 mice tended to be lower in TgCRND8 mice receiving the high protein/low carbohydrate diet than in those receiving the regular chow. Neuronal density and volume were preserved in CA1 and in the dentate gyrus.InterpretationDissociation of Aβ changes from brain mass changes raises the possibility that diet plays a role not only in modulating amyloidosis but also in modulating neuronal vulnerability. However, in the absence of a study of the effects of a high protein/low carbohydrate diet on nontransgenic mice, one cannot be certain how much, if any, of the loss of brain mass exhibited by high protein/low carbohydrate diet-fed TgCRND8 mice was due to an interaction between cerebral amyloidosis and diet. Given the recent evidence that certain factors favor the maintenance of cognitive function in the face of substantial structural neuropathology, we propose that there might also exist factors that sensitize brain neurons to some forms of neurotoxicity, including, perhaps, amyloid neurotoxicity. Identification of these factors could help reconcile the poor clinicopathological correlation between cognitive status and structural neuropathology, including amyloid pathology.
Highlights
Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by an accumulation of extracellular and cerebrovascular amyloid and intracellular aggregated tau protein [1]
The goal of this study was to evaluate the effect on Alzheimer's type neuropathology associated with one of four different diets: regular or reference commercial chow (58 kcal% carbohydrate/29 kcal% protein/13 kcal% fat), regular commercial chow (RC); high carbohydrate custom chow (60 kcal% carbohydrate/ 30 kcal% protein/10 kcal% fat), HC/LF; high fat custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate), HF/LC; high protein custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate), high protein-low carbohydrate (HP/LC); on solubilizable amyloid-β peptide (Aβ) levels and neuronal loss in TgCRND8 plaque-forming mice
Pairwise comparison of each diet to RC revealed that solubilizable Aβ42 levels were significantly increased in mice fed with HF/LC diet (RC vs F-P 147.89 vs 227.03, p = 0.014), but no difference was found between solubilizable Aβ42 levels of mice fed with HP/LC or HC/LF diets as compared to RC (HP/LC 130.89, p = 0.862; HC/LF 152.48, p = 1.000) (Figure 1)
Summary
Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by an accumulation of extracellular and cerebrovascular amyloid and intracellular aggregated tau protein [1]. The "amyloid cascade hypothesis" is one popular model of AD pathogenesis, and amyloidogenic processing by γ-secretases is enhanced by mutations in either APP, presenilin 1, or presenilin 2. In addition to the deleterious amyloidogenic pathway, an additional non-amyloidogenic pathway has been described. In this pathway, APP is first cleaved by one of several α-secretases (e.g., ADAM10, ADAM17) between positions 16 and 17 of the potential Aβ fragment, thereby precluding amyloidogenesis [2]
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