CoChat
Sign Up
Cited by 20Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid‐β

Open access
Fleeman, Rebecca M., Kuhn, Madison K., Chan, Dennis C., Proctor, Elizabeth A.·2023·Journal of Neurochemistry
DOI 10.1111/jnc.15781PMC PMC10903110
Open this paper in CoChat — free accountOpen PDF

Abstract

Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuronal metabolism and immune responses through cytokine signaling. Changes in astrocyte function because of APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk‐neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 neurons treated with media from resting APOE3 astrocytes, but treatment with astrocytic conditioned media from astrocytes challenged with amyloid‐β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not because of differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Additionally, we identified that astrocytic cytokine signatures could predict basal metabolism of neurons treated with the astrocytic conditioned media. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress.image

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/jnc.15781

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The reliance on glucose for ATP production is consistent with past studies.

    “This data tracks with our functional glycolytic assays and indicates a reliance on glucose for ATP production which is consistent with past studies 30,31,46 .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [46]

    The Results section ('Aβ treatment increases APOE4 astrocyte glycolytic ATP production'; page unavailable) reports increased glycolytic ATP production and mitochondrial glucose metabolism in APOE4 astrocytes exposed to Aβ. This supports glucose use for ATP production in that condition, but does not establish a general reliance on glucose or test whether ATP production depends on it. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 51

  1. Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, & Magistretti PJ (2010). Amyloid-β aggregates cause alterations of astrocytic metabolic phenotype: Impact on neuronal viability. Journal of Neuroscience, 30, 3326– 3338. 20203192 PMC6634099
  2. Arnaud L, Benech P, Greetham L, Stephan D, Jimenez A, Jullien N, García-González L, Tsvetkov PO, Devred F, Sancho-Martinez I, Izpisua Belmonte JC, Baranger K, Rivera S, & Nivet E (2022). APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation. Cell Reports, 40, 111200. 35977506
  3. Bayraktar OA, Bartels T, Holmqvist S, Kleshchevnikov V, Martirosyan A, Polioudakis D, Ben Haim L, AMH Y, Batiuk MY, Prakash K, Brown A, Roberts K, Paredes MF, Kawaguchi R, Stockley JH, Sabeur K, Chang SM, Huang E, Hutchinson P, … Rowitch DH (2020). Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nature Neuroscience, 23(4), 500– 509. 32203496 PMC7116562
  4. Belloy ME, Napolioni V, & Greicius MD (2019). A quarter century of APOE and Alzheimer's disease: Progress to date and the path forward. Neuron, 101, 820– 838. 30844401 PMC6407643
  5. Boué-Grabot E, & Pankratov Y (2017). Modulation of central synapses by astrocyte-released ATP and postsynaptic P2X receptors. Neural Plasticity, 2017, 1– 11. PMC5563405 28845311
  6. Boyles JK, Pitas RE, Wilson E, Mahley RW, & Taylor JM (1985). Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. The Journal of Clinical Investigation, 76, 1501– 1513. 3932467 PMC424114
  7. Butterfield DA, & Mattson MP (2020). Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease. Neurobiology of Disease, 138, 104795. 32036033 PMC7085980
  8. Choi SS, Lee HJ, Lim I, Satoh JI, & Kim SU (2014). Human astrocytes: Secretome profiles of cytokines and chemokines. PLoS One, 9, e92325. 24691121 PMC3972155
  9. 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
  10. Farmer B, Williams HC, Devanney NA, Piron MA, Nation GK, Carter DJ, Walsh AE, Khanal R, LEA Y, Kluemper JC, Hernandez G, Allenger EJ, Mooney R, Golden LR, Smith CT, Brandon JA, Gupta VA, Kern PA, Gentry MS, … Johnson LA (2021). APOE4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis. Molecular Neurodegeneration, 16, 62. 34488832 PMC8420022
  11. 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
  12. Fleeman RM, Snyder AM, Kuhn MK, Chan DC, Smith GC, Crowley NA, Arnold AC, & Proctor EA (2022). Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice. Neurobiology of Aging, 123, 154– 169. 10.1016/j.neurobiolaging.2022.11.015 36572594 PMC9892258 · DOI
  13. Gadani SP, Cronk JC, Norris GT, & Kipnis J (2012). IL-4 in the brain: A cytokine to remember. The Journal of Immunology, 189, 4213– 4219. 23087426 PMC3481177
  14. Gavillet M, Allaman I, & Magistretti PJ (2008). Modulation of astrocytic metabolic phenotype by proinflammatory cytokines. Glia, 56, 975– 989. 18383346
  15. Hasel P, Rose IVL, Sadick JS, Kim RD, & Liddelow SA (2021). Neuroinflammatory astrocyte subtypes in the mouse brain. Nature Neuroscience, 24(10), 1475– 1487. 34413515
  16. Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, … Kummer MP (2015). Neuroinflammation in Alzheimer's disease. Lancet Neurology, 14, 388– 405. 25792098 PMC5909703
  17. Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, & Paul SM (2000). Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 97, 2892– 2897. 10694577 PMC16026
  18. Huang Y, & Mahley RW (2014). Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiology of Disease, 72, 3– 12. 25173806 PMC4253862
  19. Jiang T, & Cadenas E (2014). Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell, 13, 1059– 1067. 25233945 PMC4244278
  20. Koizumi S, Fujishita K, & Inoue K (2005). Regulation of cell-to-cell communication mediated by astrocytic ATP in the CNS. Purinergic Signal, 1, 211– 217. 18404506 PMC2096541
  21. Lanfranco MF, Sepulveda J, Kopetsky G, & Rebeck GW (2021). Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation. Glia, 69, 1478– 1493. 33556209 PMC8717762
  22. Langbaum JBS, Chen K, Caselli RJ, Lee W, Reschke C, Bandy D, Alexander GE, Burns CM, Kaszniak AW, Reeder SA, Corneveaux JJ, Allen AN, Pruzin J, Huentelman MJ, Fleisher AS, & Reiman EM (2010). Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele. Archives of Neurology, 67, 462– 468. 20385913 PMC2943432
  23. LaRocca TJ, Cavalier AN, Roberts CM, Lemieux MR, Ramesh P, Garcia MA, & Link CD (2021). Amyloid beta acts synergistically as a pro-inflammatory cytokine. Neurobiology of Disease, 159, 105493. 34464705 PMC8502211
  24. Lau SF, Cao H, Fu AKY, & Ip NY (2020). Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 117, 25800– 25809. 32989152 PMC7568283
  25. Liu CC, Kanekiyo T, Xu H, & Bu G (2013). Apolipoprotein e and Alzheimer disease: Risk, mechanisms and therapy. Nature Reviews. Neurology, 9, 106– 118. 23296339 PMC3726719
  26. Liu C-C, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, & Bu G (2017). ApoE4 accelerates early seeding of amyloid pathology. Neuron, 96, 1024– 1032.e3. 29216449 PMC5948105
  27. Maezawa I, Maeda N, Montine TJ, & Montine KS (2006). Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice. Journal of Neuroinflammation, 3, 10. 16603079 PMC1502133
  28. Magistretti PJ, & Pellerin L (1999). Astrocytes couple synaptic activity to glucose utilization in the brain. News in Physiological Sciences, 14, 177– 182. 11390847
  29. Mahley RW (1988). Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science, 1979(240), 622– 630. 3283935
  30. Mahley RW (2016). Central nervous system lipoproteins. Arteriosclerosis, Thrombosis, and Vascular Biology, 36, 1305– 1315. 27174096 PMC4942259
  31. Martens YA, Zhao N, Liu CC, Kanekiyo T, Yang AJ, Goate AM, Holtzman DM, & Bu G (2022). ApoE Cascade hypothesis in the pathogenesis of Alzheimer's disease and related dementias. Neuron, 110, 1304– 1317. 10.1016/J.NEURON.2022.03.004 35298921 PMC9035117 · DOI · Paper page
  32. Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, & Tsai LH (2019). Single-cell transcriptomic analysis of Alzheimer's disease. Nature, 570, 332– 337. 31042697 PMC6865822
  33. Morris R, Kershaw NJ, & Babon JJ (2018). The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Science, 27, 1984– 2009. 30267440 PMC6237706
  34. Najm R, Jones EA, & Huang Y (2019). Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer's disease. Molecular Neurodegeneration, 14(1), 1– 13. 31186040 PMC6558779
  35. Nicholas D, Proctor EA, Raval FM, Ip BC, Habib C, Ritou E, Grammatopoulos TN, Steenkamp D, Dooms H, Apovian CM, Lauffenburger DA, & Nikolajczyk BS (2017). Advances in the quantification of mitochondrial function in primary human immune cells through extracellular flux analysis. PLoS One, 12, e0170975. 28178278 PMC5298256
  36. Nuriel T, Angulo SL, Khan U, Ashok A, Chen Q, Figueroa HY, Emrani S, Liu L, Herman M, Barrett G, Savage V, Buitrago L, Cepeda-Prado E, Fung C, Goldberg E, Gross SS, Hussaini SA, Moreno H, Small SA, & Duff KE (2017). Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology. Nature Communications, 8(1), 1– 14. PMC5684208 29133888
  37. Pellerin L, & Magistretti PJ (1994). Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proceedings of the National Academy of Sciences, 91, 10625– 10629. PMC45074 7938003
  38. Perkins M, Wolf AB, Chavira B, Shonebarger D, Meckel JP, Leung L, Ballina L, Ly S, Saini A, Jones TB, Vallejo J, Jentarra G, & Valla J (2016). Altered energy metabolism pathways in the posterior cingulate in Young adult Apolipoprotein E ε4 carriers. Journal of Alzheimer's Disease, 53, 95– 106. PMC4942726 27128370
  39. Prebil M, Jensen J, Zorec R, & Kreft M (2011). Astrocytes and energy metabolism. Archives of Physiology and Biochemistry, 117, 64– 69. 21214428
  40. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, & Hardy J (2005). Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism. Proceedings of the National Academy of Sciences of the United States of America, 102, 8299– 8302. 15932949 PMC1149416
  41. Robb JL, Hammad NA, Weightman Potter PG, Chilton JK, Beall C, & Ellacott KLJ (2020). The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling. Glia, 68, 2246– 2263. 32277522
  42. Seibenhener ML, & Wooten MW (2012). Isolation and culture of hippocampal neurons from prenatal mice. Journal of Visualized Experiments, (65), 3634. 10.3791/3634 22871921 PMC3476399 · DOI
  43. Sofroniew MV, & Vinters HV (2010). Astrocytes: Biology and pathology. Acta Neuropathologica, 119, 7– 35. 20012068 PMC2799634
  44. Stellwagen D, & Malenka RC (2006). Synaptic scaling mediated by glial TNF-α. Nature, 440, 1054– 1059. 16547515
  45. Strittmatter WJ, & Roses AD (1996). Apolipoprotein E and Alzheimer's disease. Annual Review of Neuroscience, 19, 53– 77. 8833436
  46. Thévenot EA, Roux A, Xu Y, Ezan E, & Junot C (2015). Analysis of the Human adult urinary metabolome variations with age, body mass index, and gender by implementing a comprehensive workflow for univariate and OPLS statistical analyses. Journal of Proteome Research, 14, 3322– 3335. 26088811
  47. Verkhratsky A, Nedergaard M, & Hertz L (2015). Why are astrocytes important? Neurochemical Research, 40, 389– 401. 25113122
  48. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, & Rodriguez JJ (2010). Astrocytes in Alzheimer's disease. Neurotherapeutics, 7, 399– 412. 20880504 PMC5084302
  49. Villanueva RAM, & Chen ZJ (2019). ggplot2: Elegant graphics for data analysis. Measurement: Interdisciplinary Research and Perspectives, 17(3), 160– 167. 10.1080/15366367.2019.1565254 · DOI
  50. Wood LB, Winslow AR, Proctor EA, McGuone D, Mordes DA, Frosch MP, Hyman BT, Lauffenburger DA, & Haigis KM (2015). Identification of neurotoxic cytokines by profiling Alzheimer's disease tissues and neuron culture viability screening. Scientific Reports, 5, 16622. 26564777 PMC4643219
  51. Zannis VI, Just PW, & Breslow JL (1981). Human apolipoprotein E isoprotein subclasses are genetically determined. American Journal of Human Genetics, 33, 11– 24. 7468588 PMC1684875

Cited by

Sorted by citations

Authors
Fleeman, R. M., Kuhn, M. K., Chan, D. C., & Proctor, E. A.
Affiliations
Pennsylvania State University (US)
Corresponding author
Proctor, Elizabeth A.
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2023-03
Volume
165
Issue
4
Pages
536-549
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.15781
PMC
PMC10903110
OpenAlex
W4319827707
Cited by
20
References
15
Citations by year
2026: 6 · 2025: 5 · 2024: 6 · 2023: 3
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neurochemistry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
Funders
  • National Institute of Neurological Disorders and Stroke (T32NS115667)
  • National Institute on Aging (F31AG071131, R01AG072513)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
APOE ε4, APOE3, astrocytes, amyloid-beta, Alzheimer's disease, neuronal metabolism, glycolytic metabolism, mitochondrial metabolism, astrocyte-neuron interaction, cytokine production, metabolic stress
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Cells, Cultured, Humans, Mice, Transgenic, Neurons, Amyloid beta-Peptides, Culture Media, Conditioned, Mice, Apolipoprotein E3, Apolipoprotein E4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review