Effects of Specific Multi-Nutrient Enriched Diets on Cerebral Metabolism, Cognition and Neuropathology in AβPPswe-PS1dE9 Mice

Diane Jansen,Malgorzata Miller,Dieter Lütjohann,Amanda J Kiliaan,Arend Heerschap,Leo A B Joosten,Anne Rijpma,Xiaotian T Fang,Martina P C Mutsaers,Maximilian Wiesmann,Valerio Zerbi,Ilse A C Arnoldussen,Pieter J Dederen,Laus M Broersen

doi:10.1371/journal.pone.0075393

Abstract

Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AβPPswe-PS1dE9 mice. Starting from 2 months of age, male AβPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1β mRNA levels in AβPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AβPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AβPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders.

Highlights

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects over 36 million people worldwide
While the DEU diet increased general locomotor activity and anxiety-related exploration, our results suggest that the FortasynH Connect (FC) diet could have an anxiolytic effect, since it decreased the time spent in the corners of the open field as compared to the animals on CO and DEU diets
Previous studies have shown that rats fed an n3 lc-poly-unsaturated fatty acids (PUFA) deficient diet display increased anxiety-related behavior in the open field and elevated plus maze tasks as compared to animals fed an n3 lcPUFA adequate diet [85,86]

Summary

Introduction

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects over 36 million people worldwide. Multivariate ANOVA’s (MANOVAs) were conducted with between group factors: genotype and diet, to analyze possible differences between wild-type and AbPP-PS1 mice and the different diet groups in the open field test, the probe trials of the MWM and rMWM, the body weight and brain weight, hippocampal metabolite concentrations, the amount of immature neurons, and the biochemical analyses.

Results

Conclusion