Citrulline diet supplementation improves specific age-related raft changes in wild-type rodent hippocampus
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The levels of molecules crucial for signal transduction processing change in the brain with aging. Lipid rafts are membrane microdomains involved in cell signaling. We describe here substantial biophysical and biochemical changes occurring within the rafts in hippocampus neurons from aging wild-type rats and mice. Using continuous sucrose density gradients, we observed light-, medium-, and heavy raft subpopulations in young adult rodent hippocampus neurons containing very low levels of amyloid precursor protein (APP) and almost no caveolin-1 (CAV-1). By contrast, old rodents had a homogeneous age-specific high-density caveolar raft subpopulation containing significantly more cholesterol (CHOL), CAV-1, and APP. C99-APP-Cter fragment detection demonstrates that the first step of amyloidogenic APP processing takes place in this caveolar structure during physiological aging of the rat brain. In this age-specific caveolar raft subpopulation, levels of the C99-APP-Cter fragment are exponentially correlated with those of APP, suggesting that high APP concentrations may be associated with a risk of large increases in beta-amyloid peptide levels. Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced these age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: CHOL, CAV-1, and APP concentrations were significantly lower and the C99-APP-Cter fragment was less abundant in the heavy raft subpopulation than in controls. Thus, we report substantial changes in raft structures during the aging of rodent hippocampus and describe new and promising areas of investigation concerning the possible protective effect of citrulline on brain function during aging.
KeywordsAging Amyloid precursor protein Brain Cholesterol Lipid rafts Caveolin-1 Citrulline diet Hippocampus Rodent
This work was supported by INSERM (ATC Vieillissement 2002), Université Paris Descartes (ATP aging). We thank Dr. Kenneth L. Moya for his helpful comments and his expert editing of the manuscript. We are grateful to Servane Le Plenier for her help with animal care.
- Congdon P (2006) Bayesian statistical modelling (2nd edition). Chapters 1 and 4: Chichester: Wiley, collection: Wiley series in probability and statisticsGoogle Scholar
- Gelman A, Carlin JB, Stern HS, Rubin B (2004) Bayesian data analysis. Chapter 4, 2nd edn. Chapman & Hall/CRC, Boca Raton, collection: texts in statistical scienceGoogle Scholar
- Hudry E, Van Dam D, Kulik W, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P, Cartier N (2010) Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer’s disease. Mol Ther 18:44–53PubMedCrossRefGoogle Scholar
- Igbavboa U, Eckert GP, Malo TM, Studniski AE, Johnson LN, Yamamoto N, Kobayashi M, Fujita SC, Appel TR, Muller WE, Wood WG, Yanagisawa K (2005) Murine synaptosomal lipid raft protein and lipid composition are altered by expression of human apoE 3 and 4 and by increasing age. J Neurol Sci 229–230:225–232PubMedCrossRefGoogle Scholar
- Moinard C, Walrand S, Boirie Y, Cynober L (2007) Therapeutic use of Citrulline in treatment of increased protein carbonylation-associated diseases. Pattent number 07/02090 applied the 03/22/2007Google Scholar
- Robert CP (2001) The Bayesian choice: from decision-theoretic motivations to computational implementation. Chapters 3 and 11. Springer, New-YorkGoogle Scholar
- Spiegelhalter DJ, Best NG, Carlin BR, van der Linde A (2002) Bayesian measures of model complexity and fit. J Roy Stat Soc Ser B: 583-616Google Scholar
- Yokota A, Kawasaki S, Iwano M, Nakamura C, Miyake C, Akashi K (2002) Citrulline and DRIP-1 protein (ArgE homologue) in drought tolerance of wild watermelon. Ann Bot 89 Spec No: 825-832Google Scholar