Fitz NF, Cronican A, Pham T, Fogg A, Fauq AH, Chapman R, Lefterov I, Koldamova R. Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice. J Neurosci. 2010 May 19;30(20):6862-72. PubMed.

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  1. The role of diet, and particularly dietary cholesterol, on AD risk and pathogenesis is of substantial interest and importance. The recent paper from the Lefterov and Koldamova lab that appears in the current issue of the Journal of Neuroscience sheds considerable new light on this topic, at least in mice. The authors treated APP23 mice for four months with a high-fat diet and found a remarkable fourfold increase in compact plaques in the hippocampus and cortex. There was a parallel increase in Aβ peptide levels. This is a striking demonstration of the effect of diet on amyloid deposition and clearance. Behavioral analyses revealed a diet-related impairment in memory and learning. A curious feature of the study was that there were no genotype-related differences in behavior in mice on the normal diets, a finding that conflicts with other reports. Overall, these findings verify and extend our previous understanding of the effects of high-fat intake in animal models of AD.

    One of the major findings of the study is that the simultaneous treatment of the mice on the high-fat diets with an agonist of Liver X Receptors (LXRs) led to a reversal of the memory deficits and a dramatic reduction in both plaque burden and Aβ peptide levels to levels observed in mice on a normal diet. They go on to show that LXRs act to stimulate ApoE levels and lipidation status, consistent with the established actions of these receptors. They argue that the net effect of LXR treatment is to stimulate Aβ clearance, and support this view with a very nice microdialysis study showing LXR-mediated reduction in Aβ levels in the living mouse.

    The value of this study is that it nicely weaves together a number of experimental threads into a compelling story. Importantly, the authors have provided further validation of LXRs as a therapeutic target in Alzheimer disease.

    View all comments by Gary Landreth

  2. A high-fat diet alters cellular metabolic equilibrium and influences the risk of developing several metabolic diseases. The effect of a high-fat diet on the peripheral system is well studied, but to a much less extent in the CNS. However, in the last decade, several studies attempted to look at the effect of a high-fat diet on the brain, especially in the context of AD. These studies are important in understanding the role of a high-fat diet in the potential contribution to normal brain function and to neurodegeneration. Epidemiological and clinical data suggest that a correlation exists between lifestyle, including diet, and the development of AD (1-2). Further, experiments on animal models suggest that diet may have a direct effect on the pathology of the disease (3-5). A high-fat diet significantly aggravated Aβ and tau pathologies, decreased cognitive function, and increased dyslipidemia in transgenic APP mouse models (Tg2576, APPK670N, M671L/PS1M146V, and 3xTg-AD) (6-8). Dyslipidemia is one of the major contributing factors of all high-fat induced disease processes, and hence, the roles of liver X receptors (LXRs) in these processes are central. LXR activation with synthetic agonists significantly improves cognitive functions and Aβ-related pathology in APP Tg mouse models (9-10). Though there is evidence suggesting the role of a high-fat diet in the exacerbation, and LXRs in attenuation, of Aβ-related pathology in APP Tg models, a comprehensive study on the effect of the activation of LXR in the setting of high-fat diet-induced exacerbation of Aβ pathology and cognition is missing. Also, the field lacks a complete understanding of the mechanism of the effects of LXR agonists and how they modulate Aβ metabolism, CNS lipid metabolism, and cognitive function.

    Fitz et al., in the current paper, address part of the above missing link and demonstrate that APP transgenic mice (APP23) fed for four months on a high-fat diet had significantly increased Aβ plaque load and decline in learning and memory abilities. Chronic treatment with an LXR agonist, T0, significantly decreased amyloid load, soluble and insoluble Aβ, and increased cognitive abilities caused by a high-fat diet. Further, the authors suggest that the observed amelioration of Aβ pathology is through ABCA1/ApoE clearance of Aβ, as suggested previously. This is the first work to show that high-fat diet-induced AD phenotypes can be attenuated by the activation of LXR pathways. The results of this paper also point out that activation of the LXR pathway could be a possible therapeutic target for AD and related diseases. But given the complexity of the pathways regulated by this nuclear receptor (lipid metabolism, inflammation, and innate immunity), it may be challenging to pin down all the details. Nevertheless, the work clearly shows that decrease of soluble Aβ is one of the effects of activation of the LXR pathway that is likely relevant to decreasing amyloid load. Future studies to work out all the detailed effects of LXR activation in the brain will be important to fully understand the neurobiology of this interesting pathway and how to therapeutically harness it in diseases like AD.

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    Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. PubMed.

    Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A, Mobbs CV, Hof PR, Pasinetti GM. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004 May;18(7):902-4. PubMed.

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    Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease. J Biol Chem. 2005 Feb 11;280(6):4079-88. PubMed.

    Vanmierlo T, Rutten K, Dederen J, Bloks VW, van Vark-van der Zee LC, Kuipers F, Kiliaan A, Blokland A, Sijbrands EJ, Steinbusch H, Prickaerts J, Lütjohann D, Mulder M. Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol Aging. 2011 Jul;32(7):1262-72. PubMed.

    View all comments by Philip Verghese

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