Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice
Open accessAbstract
High-fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9-month-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological, and biochemical assays. To examine the therapeutic potential of liver X receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris water maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble Aβ and soluble Aβ oligomers.In vitro experiments with primary glia demonstrate that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Aβ degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Aβ levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Aβ clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating Aβ deposition and facilitating its clearance.
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LXR agonists decrease Aβ deposition in the brain while modestly increasing apoE expression.
“LXR agonists have been shown to decrease A deposition in the brain while modestly increasing apoE expression (Koldamova et al., 2005;Zelcer et al., 2007;Fitz et al., 2010).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Fitz et al., 2010
The Results report reduced amyloid plaque load after LXR agonist treatment in APP23 mice on a high-fat diet. In the Results section on Abca1 and ApoE, ApoE protein increased approximately twofold, while the 15% increase in Apoe mRNA was not statistically significant. Thus the paper supports increased ApoE protein, but not an unqualified claim of a modest increase in ApoE expression. (LLM, conf=0.82)
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References 42 · Cited by 175
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- Cirrito JR May PC O’dell MA Taylor JW Parsadanian M Cramer JW Audia JE Nissen JS Bales KR Paul SM DeMattos RB Holtzman DM 2003 In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life J Neurosci 23 8844 8853 14523085 PMC6740389
- Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA 1993 Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families Science 261 921 923 8346443
- Cronican AA Fitz NF Pham T Fogg A Kifer B Koldamova R Lefterov I 2010 Proton pump inhibitor Lansoprazole is a nuclear liver X receptor agonist Biochem Pharmacol PMC2834822 20060385
- George AJ Holsinger RMD McLean CA Laughton KM Beyreuther K Evin G Masters CL Li QX 2004 APP intracellular domain is increased and soluble A[beta] is reduced with diet-induced hypercholesterolemia in a transgenic mouse model of Alzheimer disease Neurobiology of Disease 16 124 132 15207269
- Grefhorst A Elzinga BM Voshol PJ Plosch T Kok T Bloks VW van der Sluijs FH Havekes LM Romijn JA Verkade HJ Kuipers F 2002 Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles J Biol Chem 277 34182 34190 12097330
- Jick H Zornberg GL Jick SS Seshadri S Drachman DA 2000 Statins and the risk of dementia Lancet 356 1627 1631 11089820
- Kalaany NY Mangelsdorf DJ 2005 LXRs and FXR: The Yin and Yang of Cholesterol and Fat Metabolism Annu Rev Physiol 16460270
- Kivipelto M Helkala EL Laakso MP Hanninen T Hallikainen M Alhainen K Iivonen S Mannermaa A Tuomilehto J Nissinen A Soininen H 2002 Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease Ann Intern Med 137 149 155 12160362
- Kivipelto M Helkala EL Laakso MP Hanninen T Hallikainen M Alhainen K Soininen H Tuomilehto J Nissinen A 2001 Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study BMJ 322 1447 1451 11408299 PMC32306
- Koldamova R Lefterov I 2007 Role of LXR and ABCA1 in the Pathogenesis of Alzheimer’s Disease - Implications for a New Therapeutic Approach Curr Alzheimer Res 4 171 178 17430243
- Koldamova R Staufenbiel M Lefterov I 2005a Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice J Biol Chem 280 43224 43235 16207713
- Laffitte BA Repa JJ Joseph SB Wilpitz DC Kast HR Mangelsdorf DJ Tontonoz P 2001 LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes Proc Natl Acad Sci U S A 98 507 512 11149950 PMC14617
- Lefterov I Fitz N Cronican A Lefterov PI Staufenbiel M Koldamova RP 2009 Memory deficits in APP23/Abca1+/2 mice correlate with the level of Ab oligomers PMC2695585 19570031
- Parrott MD Greenwood CE 2007 Dietary influences on cognitive function with aging: from high-fat diets to healthful eating Ann N Y Acad Sci 1114 389 397 17986600
- Peng D Hiipakka RA Xie JT Reardon CA Getz GS Liao S 2010 Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice Atherosclerosis 208 126 133 19632679 PMC2813337
- Poirier J Davignon J Bouthillier D Kogan S Bertrand P Gauthier S 1993 Apolipoprotein E polymorphism and Alzheimer’s disease Lancet 342 697 699 8103819
- Puglielli L Tanzi RE Kovacs DM 2003 Alzheimer’s disease: the cholesterol connection Nat Neurosci 6 345 351 12658281
- Refolo LM Pappolla MA LaFrancois J Malester B Schmidt SD Thomas-Bryant T Tint GS Wang R Mercken M Petanceska SS Duff KE 2001 A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease Neurobiol Dis 8 890 899 11592856
- Refolo LM Pappolla MA Malester B LaFrancois J Bryant-Thomas T Wang R Tint GS Sambamurti K Duff K 2000 Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model Neurobiol Dis 7 321 331 10964604
- Riddell DR 2007 The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease Mol Cell Neurosci 34 621 628 17336088
- Scarmeas N Stern Y Mayeux R Luchsinger JA 2006 Mediterranean diet, Alzheimer disease, and vascular mediation Arch Neurol 63 1709 1717 17030648 PMC3024906
- Shibata N Glass CK 2009 Regulation of macrophage function in inflammation and atherosclerosis J Lipid Res 50 Suppl S277 S281 18987388 PMC2674700
- Simons M Keller P De Strooper B Beyreuther K Dotti CG Simons K 1998 Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons Proc Natl Acad Sci U S A 95 6460 6464 9600988 PMC27798
- Strittmatter WJ Saunders AM Schmechel D Pericak-Vance M Enghild J Salvesen GS Roses AD 1993 Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease Proc Natl Acad Sci U S A 90 1977 1981 8446617 PMC46003
- Sturchler-Pierrat C Abramowski D Duke M Wiederhold KH Mistl C Rothacher S Ledermann B Burki K Frey P Paganetti PA Waridel C Calhoun ME Jucker M Probst A Staufenbiel M Sommer B 1997 Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology Proc Natl Acad Sci U S A 94 13287 13292 9371838 PMC24301
- Takechi R Galloway S Pallebage-Gamarallage MM Wellington CL Johnsen RD Dhaliwal SS Mamo JC 2010 Differential effects of dietary fatty acids on the cerebral distribution of plasma-derived apo B lipoproteins with amyloid-beta Br J Nutr 103 652 662 19860996
- Thirumangalakudi L Prakasam A Zhang R Bimonte-Nelson H Sambamurti K Kindy MS Bhat NR 2008 High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice J Neurochem 106 475 485 18410513 PMC3897170
- Wahrle SE Jiang H Parsadanian M Hartman RE Bales KR Paul SM Holtzman DM 2005 Deletion of Abca1 Increases A{beta} Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease J Biol Chem 280 43236 43242 16207708
- Wahrle SE Jiang H Parsadanian M Legleiter J Han X Fryer JD Kowalewski T Holtzman DM 2004 ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE J Biol Chem 279 40987 40993 15269217
- Zandi PP Sparks DL Khachaturian AS Tschanz J Norton M Steinberg M Welsh-Bohmer KA Breitner JC 2005 Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study Arch Gen Psychiatry 62 217 224 15699299
- Zanotti I Favari E Sposito AC Rothblat GH Bernini F 2004 Pitavastatin increases ABCA1-mediated lipid efflux from Fu5AH rat hepatoma cells Biochem Biophys Res Commun 321 670 674 15358158
- Zelcer N Khanlou N Clare R Jiang Q Reed-Geaghan EG Landreth GE Vinters HV Tontonoz P 2007 Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors Proc Natl Acad Sci U S A 104 10601 10606 17563384 PMC1890560
- Authors
- Fitz, N. F., Cronican, A., Pham, T., Fogg, A., Fauq, A. H., Chapman, R., Lefterov, I., & Koldamova, R.
- Affiliations
- University of Pittsburgh (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Lefterov, Iliya
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-05-19
- Volume
- 30
- Issue
- 20
- Pages
- 6862-6872
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2883862
- OpenAlex
- W2088411318
- Cited by
- 175
- References
- 42
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 7 · 2019: 7 · 2018: 10 · 2017: 16 · 2016: 14 · 2015: 12 · 2014: 11 · 2013: 21 · 2012: 18
- FWCI
- 12.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh (P50 AG005133)
- National Institutes of Health (AG005133)
- University of California, Irvine
- National Institute on Aging (AG027973, AG-005133, AG031956, P50AG005133, R01AG027973, R21AG031956)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- liver X receptor agonist, T0901317, Alzheimer's disease, amyloid pathology, amyloid-beta clearance, high-fat diet, APP23 mice, memory impairment, ABCA1, microglia, glia, amyloid plaques, cognitive decline
- MeSH terms
- Liver X Receptors, Benzenesulfonamides, Age Factors, Amyloid, Analysis of Variance, Animals, Cells, Cultured, Cerebral Cortex, Dietary Fats, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Fluorocarbons, Hippocampus, Humans, Hydrocarbons, Fluorinated, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Peptide Fragments, Retention, Psychology, RNA, Messenger, Sulfonamides, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Culture Media, Conditioned, Microdialysis, Microglia, ATP-Binding Cassette Transporters, Maze Learning, Mice, Orphan Nuclear Receptors, ATP Binding Cassette Transporter 1
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