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Cited by 28Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Thy1-ApoE4/C/EBPβ double transgenic mice act as a sporadic model with Alzheimer’s disease

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Qian, Zhengjiang, Wang, ZhiHao, Li, Bowei, Meng, Xin, Kuang, Zhonghua, Li, Yanjiao, Yang, Yongfeng, Ye, Keqiang·2024·Molecular Psychiatry
DOI 10.1038/s41380-024-02565-xPMC PMC11449781
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Abstract

Early onset familial Alzheimer’s disease (FAD) with APP, PS1/2 (presenilins) mutation accounts for only a small portion of AD cases, and most are late-onset sporadic. However, majority of AD mouse models are developed to mimic the genetic cause of human AD by overexpressing mutated forms of human APP, PS1/2, and/or Tau protein, though there is no Tau mutation in AD, and no single mouse model recapitulates all aspects of AD pathology. Here, we report Thy1-ApoE4/C/EBPβ double transgenic mouse model that demonstrates key AD pathologies in an age-dependent manner in absence of any human APP or PS1/2 mutation. Using the clinical diagnosis criteria, we show that this mouse model exhibits tempo-spatial features in AD patient brains, including progressive cognitive decline associated with brain atrophy, which is accompanied with extensive neuronal degeneration. Remarkably, the mice display gradual Aβ aggregation and neurofibrillary tangles formation in the brain validated by Aβ PET and Tau PET. Moreover, the mice reveal widespread neuroinflammation as shown in AD brains. Hence, Thy1-ApoE4/C/EBPβ mouse model acts as a sporadic AD mouse model, reconstituting the major AD pathologies.

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  • A hallmark of the ApoE4 mouse phenotype is reduced neuronal complexity, characterized by fewer, shorter, and less branched dendrites, including reduced dendritic spine density in the hippocampus and entorhinal cortex.

    “A hallmark of the ApoE4 mouse phenotype is reduced neuronal complexity, characterized by fewer, shorter, and less branched dendrites. This includes a major reduction in dendritic spine density in the hippocampus (specifically the dentate gyrus and CA1 regions) and the entorhinal cortex [26–28].”

    From Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice (2026) · cites this paper as [28]

    The Discussion reports attenuated dendritic arborization and spines in hippocampal CA1 neurons of nine-month-old Thy1-ApoE4/C/EBPβ double-transgenic mice compared with wild-type littermates. It does not report reduced spine density in the dentate gyrus or entorhinal cortex, or establish these findings as a general ApoE4 mouse phenotype. The Fig. 4 caption names those regions in relation to Aβ distribution, not spine density. (LLM, conf=0.86)

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  1. [1]Selkoe DJ. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimer’s Dis. 2001;3:75–80. 12214075 · DOI
  2. [2]Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. 25792098 PMC5909703 · DOI · Paper page
  3. [3]DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64. 2360787 · DOI · Paper page
  4. [5]Flood DG, Coleman PD. Hippocampal plasticity in normal aging and decreased plasticity in Alzheimer’s disease. Progr Brain Res. 1990;83:435–43. 2203107 · DOI
  5. [8]Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80. 1789684 · DOI · Paper page
  6. [9]Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P. Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging. 1995;16:285–98. discussion 298-304 7566338 · DOI · Paper page
  7. [10]Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. 2021;397:1577–90. 33667416 PMC8354300 · DOI · Paper page
  8. [11]Chartier-Harlin MC, Parfitt M, Legrain S, Pérez-Tur J, Brousseau T, Evans A, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: analysis of the 19q13.2 chromosomal region. Human Mol Genet. 1994;3:569–74. 8069300 · DOI
  9. [12]Houlden H, Crook R, Backhovens H, Prihar G, Baker M, Hutton M, et al. ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer’s disease families. Am J Med Genet. 1998;81:117–21. 9514597 · DOI
  10. [13]Tanzi RE, Bertram L. New frontiers in Alzheimer’s disease genetics. Neuron. 2001;32:181–4. 11683989 · DOI
  11. [14]Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18. 23296339 PMC3726719 · DOI · Paper page
  12. [15]Lynch JR, Tang W, Wang H, Vitek MP, Bennett ER, Sullivan PM, et al. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem. 2003;278:48529–33. 14507923 · DOI · Paper page
  13. [16]Ringman JM, Elashoff D, Geschwind DH, Welsh BT, Gylys KH, Lee C, et al. Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch Neurol. 2012;69:757–64. 22689192 PMC3668092 · DOI
  14. [18]Han SH, Einstein G, Weisgraber KH, Strittmatter WJ, Saunders AM, Pericak-Vance M, et al. Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J Neuropathol Exp Neurol. 1994;53:535–44. 8083695 · DOI · Paper page
  15. [19]Bao F, Arai H, Matsushita S, Higuchi S, Sasaki H. Expression of apolipoprotein E in normal and diverse neurodegenerative disease brain. Neuroreport. 1996;7:1733–9. 8905654 · DOI
  16. [20]Boschert U, Merlo-Pich E, Higgins G, Roses AD, Catsicas S. Apolipoprotein E expression by neurons surviving excitotoxic stress. Neurobiol Dis. 1999;6:508–14. 10600406 · DOI
  17. [21]Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 2006;26:4985–94. 16687490 PMC6674234 · DOI · Paper page
  18. [22]Darmanis S, Sloan SA, Zhang Y, Enge M, Caneda C, Shuer LM, et al. A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci USA. 2015;112:7285–90. 26060301 PMC4466750 · DOI · Paper page
  19. [23]Zalocusky KA, Najm R, Taubes AL, Hao Y, Yoon SY, Koutsodendris N, et al. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease. Nature Neurosci. 2021;24:786–98. 33958804 PMC9145692 · DOI · Paper page
  20. [24]Cardinaux JR, Allaman I, Magistretti PJ. Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and C/EBPdelta in astrocytes. Glia. 2000;29:91–97. 10594926 · DOI
  21. [25]Cortes-Canteli M, Aguilar-Morante D, Sanz-Sancristobal M, Megias D, Santos A, Perez-Castillo A. Role of C/EBPβ transcription factor in adult hippocampal neurogenesis. PLoS ONE. 2011;6:e24842. 22003384 PMC3189174 · DOI
  22. [26]Wang ZH, Gong K, Liu X, Zhang Z, Sun X, Wei ZZ, et al. C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nature Commun. 2018;9:1784. 29725016 PMC5934399 · DOI
  23. [27]Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nature Med. 2014;20:1254–62. 25326800 PMC4224595 · DOI · Paper page
  24. [28]Zhang Z, Song M, Liu X, Su Kang S, Duong DM, Seyfried NT, et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat Commun. 2015;6:8762. 26549211 PMC4659940 · DOI
  25. [29]Wang H, Liu X, Chen S, Ye K. Spatiotemporal activation of the C/EBPβ/δ-secretase axis regulates the pathogenesis of Alzheimer’s disease. Proc Natl Acad Sci USA. 2018;115:E12427–e12434. 30530690 PMC6310855 · DOI
  26. [30]Strohmeyer R, Shelton J, Lougheed C, Breitkopf T. CCAAT-enhancer binding protein-β expression and elevation in Alzheimer’s disease and microglial cell cultures. PLoS ONE. 2014;9:e86617. 24466171 PMC3899300 · DOI
  27. [31]Xia Y, Wang ZH, Zhang J, Liu X, Yu SP, Ye KX, et al. C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer’s disease. Mol Psychiatry. 2021;26:6002–22. 33339957 PMC8758498 · DOI
  28. [32]Wang ZH, Xia Y, Liu P, Liu X, Edgington-Mitchell L, Lei K, et al. ApoE4 activates C/EBPβ/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer’s disease. Prog Neurobiol. 2021;202:102032. 33716161 PMC8627566 · DOI
  29. [33]Ndoja A, Reja R, Lee SH, Webster JD, Ngu H, Rose CM, et al. Ubiquitin ligase COP1 suppresses neuroinflammation by degrading c/EBPβ in microglia. Cell. 2020;182:1156–1169.e1112. 32795415 · DOI
  30. [34]Wang ZH, Xia Y, Wu Z, Kang SS, Zhang JC, Liu P, et al. Neuronal ApoE4 stimulates C/EBPβ activation, promoting Alzheimer’s disease pathology in a mouse model. Prog Neurobiol. 2022;209:102212. 34958873 · DOI
  31. [35]Lee JE, Han PL. An update of animal models of Alzheimer disease with a reevaluation of plaque depositions. Exp Neurobiol. 2013;22:84–95. 23833557 PMC3699678 · DOI
  32. [36]Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–21. 12895417 · DOI · Paper page
  33. [37]Xia Y, Wang ZH, Zhang Z, Liu X, Yu SP, Wang JZ, et al. Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer’s disease. Prog Neurobiol. 2021;204:102113. 34166772 PMC8627568 · DOI
  34. [38]Dallaire-Théroux C, Callahan BL, Potvin O, Saikali S, Duchesne S. Radiological-pathological correlation in Alzheimer’s disease: systematic review of antemortem magnetic resonance imaging findings. J Alzheimer’s Dis. 2017;57:575–601. 28282807 · DOI
  35. [39]Chiquita S, Ribeiro M, Castelhano J, Oliveira F, Sereno J, Batista M, et al. A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss. Hum Mol Genet. 2019;28:2174–88. 30816415 PMC6586150 · DOI · Paper page
  36. [41]Ahlemeyer B, Halupczok S, Rodenberg-Frank E, Valerius KP, Baumgart-Vogt E. Endogenous murine amyloid-β peptide assembles into aggregates in the aged C57BL/6J mouse suggesting these animals as a model to study pathogenesis of amyloid-β plaque formation. J Alzheimer’s Dis. 2018;61:1425–50. 29376876 · DOI
  37. [42]Xu G, Ran Y, Fromholt SE, Fu C, Yachnis AT, Golde TE, et al. Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits. Acta Neuropathol Commun. 2015;3:72. 26566997 PMC4644287 · DOI · Paper page
  38. [43]Krohn M, Bracke A, Avchalumov Y, Schumacher T, Hofrichter J, Paarmann K, et al. Accumulation of murine amyloid-β mimics early Alzheimer’s disease. Brain. 2015;138:2370–82. 25991605 · DOI
  39. [45]Adams SJ, Crook RJ, Deture M, Randle SJ, Innes AE, Yu XZ, et al. Overexpression of wild-type murine tau results in progressive tauopathy and neurodegeneration. Am J Pathol. 2009;175:1598–609. 19717642 PMC2751556 · DOI
  40. [47]Lv X, Li W, Luo Y, Wang D, Zhu C, Huang ZX, et al. Exploring the differences between mouse mAβ(1-42) and human hAβ(1-42) for Alzheimer’s disease related properties and neuronal cytotoxicity. Chem Commun. 2013;49:5865–7. 23700581 · DOI
  41. [48]Dyrks T, Dyrks E, Masters CL, Beyreuther K. Amyloidogenicity of rodent and human beta A4 sequences. FEBS Lett. 1993;324:231–6. 8508926 · DOI
  42. [49]Gonzalez-Ortiz F, Turton M, Kac PR, Smirnov D, Premi E, Ghidoni R, et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain. 2023;146:1152–65. 36572122 PMC9976981 · DOI
  43. [50]Simrén J, Brum WS, Ashton NJ, Benedet AL, Karikari TK, Kvartsberg H, et al. CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals. Alzheimer’s Res Ther. 2022;14:192. 36544221 PMC9773470 · DOI
  44. [52]Goedert M. NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein. Science. 2015;349:1255555. 26250687 · DOI
  45. [55]Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science. 2008;321:1686–9. 18802001 · DOI · Paper page
  46. [57]Tzioras M, McGeachan RI, Durrant CS, Spires-Jones TL. Synaptic degeneration in Alzheimer disease. Nature Rev Neurol. 2023;19:19–38. 36513730 · DOI · Paper page
  47. [58]Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2000;97:2892–7. 10694577 PMC16026 · DOI · Paper page
  48. [59]Fagan AM, Watson M, Parsadanian M, Bales KR, Paul SM, Holtzman DM. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2002;9:305–18. 11950276 · DOI · Paper page
  49. [60]Jucker M, Walker LC. Alzheimer’s disease: from immunotherapy to immunoprevention. Cell. 2023;186:4260–70. 37729908 PMC10578497 · DOI · Paper page
  50. [61]Xiong J, Kang SS, Wang M, Wang Z, Xia Y, Liao J, et al. FSH and ApoE4 contribute to Alzheimer’s disease-like pathogenesis via C/EBPβ/δ-secretase in female mice. Nature Commun. 2023;14:6577. 37852961 PMC10584868 · DOI
  51. [62]Koutsodendris N, Blumenfeld J, Agrawal A, Traglia M, Grone B, Zilberter M, et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nature Aging. 2023;3:275–96. 37118426 PMC10154214 · DOI · Paper page
  52. [64]Qian Z, Li H, Yang H, Yang Q, Lu Z, Wang L, et al. Osteocalcin attenuates oligodendrocyte differentiation and myelination via GPR37 signaling in the mouse brain. Sci Adv. 2021;7:eabi5811. 34678058 PMC8535816 · DOI
  53. [65]Qian Z, Li B, Meng X, Liao J, Wang G, Li Y, et al. Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer’s disease in mice. Neuropsychopharmacology 2024;49:620–630 PMC10789813 38030711
  54. [66]Casali BT, Landreth GE. Aβ Extraction from murine brain homogenates. Bio-protocol 2016;6:e1787. PMC5431584 28516120
  55. [67]Sahara N, Kimura T. Biochemical properties of pathology-related tau species in tauopathy brains: an extraction protocol for tau oligomers and aggregates. Methods Mol Biol. 2018;1779:435–45. 29886548 · DOI

Cited by

Sorted by citations

Authors
Qian, Z., Wang, Z., Li, B., Meng, X., Kuang, Z., Li, Y., Yang, Y., & Ye, K.
Affiliations
Chinese Academy of Sciences (CN)
Corresponding author
Ye, Keqiang
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2024-04-24
Volume
29
Issue
10
Pages
3040-3055
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-024-02565-x
PMC
PMC11449781
OpenAlex
W4395116435
Cited by
28
References
12
Citations by year
2026: 13 · 2025: 12 · 2024: 3
FWCI
7.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (32200928, 32330040)
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
Alzheimer's disease, sporadic Alzheimer's disease, amyloid-beta aggregation, neurofibrillary tangles, neuroinflammation, cognitive decline, brain atrophy, neurodegeneration, tau PET, mouse model
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Mutation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Neurofibrillary Tangles, tau Proteins, CCAAT-Enhancer-Binding Protein-beta, Mice, Apolipoprotein E4

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