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Cited by 18Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [18F]FDG-μPET Study

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Venzi, Marcello, Tóth, Miklós, Häggkvist, Jenny, Bogstedt, Anna, Rachalski, Adeline, Mattsson, Anna, Frumento, Paolo, Farde, Lars·2017·Journal of Alzheimer's Disease Reports
DOI 10.3233/adr-170006PMC PMC6159693
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Abstract

Background: The Apolipoprotein E (ApoE) alleles ɛ2, ɛ3, and ɛ4 are known to differentially modulate cerebral glucose metabolism and the risk for Alzheimer’s disease (AD) via both amyloid-β (Aβ)-dependent and independent mechanisms. Objective: We investigated the influence of ApoE on cerebral glucose metabolism in humanized APOE Targeted Replacement (TR) mice at ages that precede the comparison of Aβ parenchymal deposits in APOE4-TR mice. Methods: Fludeoxyglucose ([18 F]FDG) positron emission tomography (PET) measures were performed longitudinally in homozygous APOE-TR mice (APOE2, APOE3, APOE4; n = 10 for each group) at 3, 5, 11, and 15 months. Results were quantified using standard uptake values and analyzed statistically using a linear mixed effects model. Levels of the Aβ 40 and Aβ 42 peptides were quantified ex vivo using enzyme-linked immunosorbent assay (ELISA) at 15 months in the same animals. Results: APOE2 mice (versus APOE3) showed a significant increase in glucose metabolism starting at 6 months, peaking at 9 months. No evidence of hypometabolism was apparent in any region or time point for APOE4 mice, which instead displayed a hypermetabolism at 15 months. Whole brain soluble Aβ 40 and Aβ 42 levels were not significantly different between genotypes at 15 months. Conclusions: Introduction of human APOE alleles ɛ2 and ɛ4 is sufficient to produce alterations in brain glucose metabolism in comparison to the control allele ɛ3, without a concomitant alteration in Aβ 40 and Aβ 42 levels. These results suggest novel Aβ-independent metabolic phenotypes conferred by ɛ2 and ɛ4 alleles and have important implications for preclinical studies using TR-mice.

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  • Previous studies have already linked APOE4 to increased (hyper-)metabolism in young individuals.

    “However, previous studies have already linked APOE4 to increased (hyper-)metabolism in young individuals.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [47]

    The Introduction reports reduced brain metabolism in APOE4 carriers aged 20–39, not increased metabolism. The Discussion reports hypermetabolism only in APOE4-targeted replacement mice at 15 months; at the first measurement, 3 months, there was no genotype effect on brain glucose metabolism. No page numbers are available in our copy. (LLM, conf=0.88)

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  • Several studies using APOE4 KI mouse models that do not yet show features of neurodegeneration observed a hypermetabolism caused by APOE4.

    “Further, several studies using APOE4 KI mouse models, that do not yet show features of neurodegeneration, observed a hypermetabolism caused by APOE4 [47,48].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [47]

    The Discussion reports hypermetabolism in APOE4 targeted-replacement mice at 15 months, and the Introduction says the study was conducted before amyloid plaques appear. But the paper establishes absence of plaques and no significant whole-brain soluble Aβ difference, not absence of all features of neurodegeneration; its Introduction also describes earlier synaptic and dendritic deficits in these mice. (LLM, conf=0.84)

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Research works printed but not linked: 43

  1. [1]Mahley RW (1988) Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science 240, 622– 630. 3283935
  2. [2]Srivastava RA, Bhasin N, Srivastava N (1996) Apolipoprotein E gene expression in various tissues of mouse and regulation by estrogen. Biochem Mol Biol Int 38, 91– 101. 8932523
  3. [3]Corbo RM, Scacchi R (1999) Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a “thrifty” allele? Ann Hum Genet 63, 301– 310. 10738542
  4. [4]Mahley RW, Rall SCJ (2000) Apolipoprotein E: Far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1, 507– 537. 11701639
  5. [5]Huang Y, Mahley RW (2014) Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis 72, 3– 12. 25173806 PMC4253862
  6. [6]Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci USA 103, 5644– 5651. 16567625 PMC1414631
  7. [7]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
  8. [8]Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimerdisease. Nat Genet 7, 180– 184. 7920638
  9. [9]Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between Apolipoprotein E genotype and Alzheimer disease: A meta-analysis. JAMA 278, 1349– 1356. 9343467
  10. [10]McGeer EG, Peppard RP, McGeer PL, Tuokko H, Crockett D, Parks R, Akiyama H, Calne DB, Beattie BL, Harrop R (1990) 18Fluorodeoxyglucose positron emission tomography studies in presumed Alzheimer cases, including 13 serial scans. Can J Neurol Sci 17, 1– 11. 2311010
  11. [12]Mielke R, Herholz K, Grond M, Kessler J, Heiss WD (1994) Clinical deterioration in probable Alzheimer’s disease correlates with progressive metabolic impairment of association areas. Dementia 5, 36– 41. 8156085
  12. [13]Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE (1995) A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 36, 1238– 1248. 7790950
  13. [14]Small GW, Mazziotta JC, Collins MT, Baxter LR, Phelps ME, Mandelkern MA, Kaplan A, La Rue A, Adamson CF, Chang L (1995) Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 273, 942– 947. 7884953
  14. [15]Reiman EM, Caselli RJ, Yun LS, Chen KW, Bandy D, Minoshima S, Thibodeau SN, Osborne D (1996) Preclinical evidence of Alzheimer’s disease in persons homozygous for the ɛ-4 allele for Apolipoprotein E. N Engl J Med 334, 752– 758. 8592548
  15. [16]Lowe VJ, Weigand SD, Senjem ML, Vemuri P, Jordan L, Kantarci K, Boeve B, Jack CR, Knopman D, Petersen RC (2014) Association of hypometabolism and amyloid levels in aging, normal subjects. Neurology 82, 1959– 1967. 24793183 PMC4105262
  16. [17]Altmann A, Ng B, Landau SM, Jagust WJ, Greicius MD (2015) Regional brain hypometabolism is unrelated to regional amyloid plaque burden. Brain 138, 3734– 3746. 26419799 PMC4806718
  17. [19]Holtzman D, Herz J (2012) Apolipoprotein E and apolipoprotein receptors: Normal biology and roles in Alzheimer’s disease. Cold Spring Harb Perspect Med 2, a006312. 22393530 PMC3282491
  18. [22]Huang Y (2010) Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med 16, 287– 294. 20537952
  19. [23]Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 101, 284– 289. 14688411 PMC314177
  20. [24]Sullivan PM, Knouff C, Najib J, Reddick RL, Quarfordt SH (1997) Targeted replacement of the mouse Apolipoprotein E gene with the common human. J Biol Chem 272, 17972– 17980. 9218423
  21. [26]Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, Sullivan PM, Maeda N (1999) Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest 103, 1579– 1586. 10359567 PMC408371
  22. [27]Sullivan PM, Mace BE, Estrada JC, Schmechel DE, Alberts MJ (2008) Human Apolipoprotein E4 targeted replacement mice show increased prevalence of intracerebral hemorrhage associated with vascular amyloid deposition. J Stroke Cerebrovasc Dis 17, 303– 311. 18755411
  23. [28]Trommer BL, Shah C, Yun SH, Gamkrelidze G, Pasternak ES, Ye GL, Sotak M, Sullivan PM, Pasternak JF, LaDu MJ (2004) ApoE isoform affects LTP in human targeted replacement mice. Neuroreport 15, 2655– 2658. 15570172
  24. [29]Klein RC, Mace BE, Moore SD, Sullivan PM (2010) Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2. Neuroscience 171, 1265– 1272. 20951774 PMC2991419
  25. [30]Ong Q-R, Chan ES, Lim M-L, Cole GM, Wong B-S (2014) Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice. Sci Rep 4, 3754. 24435134 PMC3894554
  26. [31]Tesseur I, Van Dorpe J, Bruynseels K, Bronfman F, Sciot R, Van Lommel A, Van Leuven F (2000) Prominent opathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol 157, 1495– 1510. 11073810 PMC1885744
  27. [32]James R, Searcy JL, Le Bihan T, Martin SF, Gliddon CM, Povey J, Deighton RF, Kerr LE, McCulloch J, Horsburgh K (2012) Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challenge. J Cereb Blood Flow Metab 32, 164– 176. 21878944 PMC3323298
  28. [33]Wolf AB, Caselli RJ, Reiman EM, Valla J (2013) APOE and neuroenergetics: An emerging paradigm in Alzheimer’s disease. Neurobiol Aging 34, 1007– 1017. 23159550 PMC3545040
  29. [34]Tai LM, Youmans KL, Jungbauer L, Yu C, Ladu MJ (2011) Introducing Human APOE into Aβ Transgenic Mouse Models. Int J Alzheimers Dis 2011, 810981. 22028984 PMC3199079
  30. [35]Mortensen EL, Hogh P (2001) A gender difference in the association between APOE genotype and age-related cognitive decline. Neurology 57, 89– 95. 11445633
  31. [36]Eketjall S, Janson J, Jeppsson F, Svanhagen A, Kolmodin K, Gustavsson S, Radesater A-C, Eliason K, Briem S, Appelkvist P, Niva C, Berg A-L, Karlstrom S, Swahn B-M, Falting J (2013) AZ-4217: A high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice. J Neurosci 33, 10075– 10084. 23761903 PMC6618391
  32. [37]Ma Y, Hof PR, Grant SC, Blackband SJ, Bennett R, Slatest L, Mcguigan MD, Benveniste H (2005) A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy. Neuroscience 135, 1203– 1215. 16165303
  33. [39]Knopman DS, Jack CR, Wiste HJ, Lundt ES, Weigand SD, Vemuri P, Lowe VJ, Kantarci K, Gunter JL, Senjem ML, Mielke MM, Roberts RO, Boeve BF, Petersen RC (2014) 18F-fluorodeoxyglucose positron emission tomography, aging, and apolipoprotein E genotype in cognitively normal persons. Neurobiol Aging 35, 2096– 2106. 24702820 PMC4053507
  34. [40]Rimajova M, Lenzo NP, Wu J-S, Bates KA, Campbell A, Dhaliwal SS, McCarthy M, Rodrigues M, Paton A, Rowe C, Foster JK, Martins RN (2008) Fluoro-2-deoxy-D-glucose (FDG)-PET in APOE epsilon 4 carriers in the Australian population. J Alzheimers Dis 13, 137– 146. 18376055
  35. [42]Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A, Rapoport JL, Giedd JN (2007) Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: An observational study. Lancet Neurol 6, 494– 500. 17509484
  36. [45]Fouquet M, Besson FL, Gonneaud J, La Joie R, Chételat G (2014) Imaging brain effects of APOE4 in cognitively normal individuals across the lifespan. Neuropsychol Rev 24, 290– 299. 25146994
  37. [47]Chan ES, Chen C, Cole GM, Wong B-S (2015) Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice. Sci Rep 5, 13842. 26346625 PMC4561911
  38. [48]Kuhel DG, Konaniah ES, Basford JE, McVey C, Goodin CT, Chatterjee TK, Weintraub NL, Hui DY (2013) Apolipoprotein E2 accentuates postprandial inflammation and diet-induced obesity to promote hyperinsulinemia in mice. Diabetes 62, 382– 391. 22961083 PMC3554349
  39. [50]Salomon-Zimri S, Liraz O, Michaelson DM (2015) Behavioral testing affects the phenotypic expression of APOE ɛ3 and APOE ɛ4 in targeted replacement mice and reduces the differences between them. Alzheimers Dement (Amst) 1, 127– 135. 27239500 PMC4876887
  40. [51]Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, Phelps ME, Weber WA (2006) Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med 47, 999– 1006. 16741310
  41. [52]Huebbe P, Dose J, Schloesser A, Campbell G, Glüer CC, Gupta Y, Ibrahim S, Minihane AM, Baines JF, Nebel A, Rimbach G (2015) Apolipoprotein E (APOE) genotype regulates body weight and fatty acid utilization-Studies in gene-targeted replacement mice. Mol Nutr Food Res 59, 334– 343. 25381750
  42. [53]Lam TKT, Gutierrez-Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L (2007) Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat Med 13, 171– 180. 17273170
  43. [54]Shinohara M, Kanekiyo T, Yang L, Linthicum D, Shinohara M, Fu Y, Price L, Frisch-Daiello JL, Han X, Fryer JD, Bu G (2016) APOE2 eases cognitive decline during aging: Clinical and preclinical evaluations. Ann Neurol. 10.1002/ana.24628 PMC5010530 26933942 · DOI · Paper page

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Authors
Venzi, M., Tóth, M., Häggkvist, J., Bogstedt, A., Rachalski, A., Mattsson, A., Frumento, P., & Farde, L.
Affiliations
  • Karolinska University Hospital (SE)
  • Karolinska Institutet (SE)
Corresponding author
Venzi, Marcello
ORCID
Venue
Journal of Alzheimer's Disease Reports
Publisher
SAGE Publications
Published
2017-08-10
Volume
1
Issue
1
Pages
169-180
ISSN
2542-4823 (ISSN-L)
DOI
10.3233/adr-170006
PMC
PMC6159693
OpenAlex
W2748872907
Cited by
18
References
10
Citations by year
2026: 3 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 4 · 2018: 1
FWCI
0.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Alzheimer s Disease Reports (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • AstraZeneca
  • Karolinska Institutet
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, APOE ε2, APOE ε3, APOE ε4, brain glucose metabolism, humanized mice, amyloid-beta, Aβ40, amyloid-beta 42, hypermetabolism, hypometabolism, Alzheimer's disease risk, 18F-FDG PET

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