Home LiteratureArticle Details
PMID: 16039562 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Abeta42 is essential for parenchymal and vascular amyloid deposition in mice.

Neuron ·Vol. 47 ·No. 2 ·2005-07-21 ·Pages 191-199

McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, DeLucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T

Abstract

Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.

MeSH Terms
Age Factors Amyloid beta-Peptides/genetics,metabolism Amyloid beta-Protein Precursor/genetics,metabolism Animals Benzothiazoles Blood Vessels/metabolism,pathology,ultrastructure Blotting, Northern/methods Blotting, Western/methods Brain/metabolism,pathology,ultrastructure Cerebral Amyloid Angiopathy/metabolism,pathology Enzyme-Linked Immunosorbent Assay/methods Female Glial Fibrillary Acidic Protein/metabolism Humans Immunohistochemistry/methods Immunoprecipitation/methods In Situ Hybridization/methods Male Mass Spectrometry/methods Mice Mice, Transgenic Microscopy, Electron, Transmission/methods Mutation Peptide Fragments/analysis,genetics,metabolism Pia Mater/metabolism,pathology,ultrastructure Plaque, Amyloid/metabolism,pathology Thiazoles/metabolism
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Benzothiazoles Glial Fibrillary Acidic Protein Peptide Fragments Thiazoles amyloid beta-protein (1-40) amyloid beta-protein (1-42) thioflavin T
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
McGowan Eileen
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Pickford Fiona
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Kim Jungsu
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Onstead Luisa
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Eriksen Jason
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Yu Cindy
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Skipper Lisa
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Murphy M Paul
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Beard Jenny
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Das Pritam
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Jansen Karen
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
DeLucia Michael
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Lin Wen-Lang
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Dolios Georgia
Department of Human Genetics Mount Sinai School of Medicine New York, New York 10029.
Wang Rong
Department of Human Genetics Mount Sinai School of Medicine New York, New York 10029.
Eckman Christopher B
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Dickson Dennis W
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Hutton Mike
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
Hardy John
Laboratory of Neurogenetics National Institute on Aging National Institutes of Health Bethesda, Maryland 20892.
Golde Todd
Department Neuroscience Mayo Clinic College of Medicine Jacksonville, Florida 32224.
References (39)
39 references, click to expand
  1. Pathways towards and away from Alzheimer's disease.
    Nature. 2004 Aug 5;430(7000):631-9 PMID: 15295589
  2. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis.
    Nat Neurosci. 2004 Sep;7(9):954-60 PMID: 15311281
  3. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease.
    Science. 1989 Jul 28;245(4916):417-20 PMID: 2474201
  4. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease.
    Biochemistry. 1993 May 11;32(18):4693-7 PMID: 8490014
  5. Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie?
    Cell. 1993 Jun 18;73(6):1055-8 PMID: 8513491
  6. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43).
    Neuron. 1994 Jul;13(1):45-53 PMID: 8043280
  7. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.
    Nature. 1995 Feb 9;373(6514):523-7 PMID: 7845465
  8. The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice.
    Nat Genet. 1995 Jan;9(1):21-30 PMID: 7704018
  9. Amyloid beta protein (A beta) in Alzheimer's disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43).
    J Biol Chem. 1995 Mar 31;270(13):7013-6 PMID: 7706234
  10. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.
    Science. 1996 Oct 4;274(5284):99-102 PMID: 8810256
  11. The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry.
    J Biol Chem. 1996 Dec 13;271(50):31894-902 PMID: 8943233
  12. A vector for expressing foreign genes in the brains and hearts of transgenic mice.
    Genet Anal. 1996 Dec;13(6):159-63 PMID: 9117892
  13. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.
    Neuron. 1997 Oct;19(4):939-45 PMID: 9354339
  14. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.
    Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13287-92 PMID: 9371838
  15. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.
    Nat Med. 1998 Jan;4(1):97-100 PMID: 9427614
  16. The role of A beta 42 in Alzheimer's disease.
    J Physiol Paris. 1998 Jun-Aug;92(3-4):289-92 PMID: 9789825
  17. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease.
    Trends Cell Biol. 1998 Nov;8(11):447-53 PMID: 9854312
  18. Alzheimer's disease: genetic studies and transgenic models.
    Annu Rev Genet. 1998;32:461-93 PMID: 9928488
  19. A stop-codon mutation in the BRI gene associated with familial British dementia.
    Nature. 1999 Jun 24;399(6738):776-81 PMID: 10391242
  20. Interaction of human and mouse Abeta peptides.
    J Neurochem. 2004 Dec;91(6):1398-403 PMID: 15584916
  21. Interaction between A beta(1-42) and A beta(1-40) in Alzheimer's beta-amyloid fibril formation in vitro.
    Biochemistry. 1999 Nov 23;38(47):15514-21 PMID: 10569934
  22. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease.
    Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15233-8 PMID: 10611368
  23. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7 PMID: 10694577
  24. A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor.
    Nat Med. 2000 Apr;6(4):397-404 PMID: 10742146
  25. A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred.
    Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4920-5 PMID: 10781099
  26. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
    J Neurosci. 2000 Jun 1;20(11):4050-8 PMID: 10818140
  27. Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease.
    Biochim Biophys Acta. 2000 Jul 26;1502(1):172-87 PMID: 10899442
  28. Amyloidogenesis in familial British dementia is associated with a genetic defect on chromosome 13.
    Ann N Y Acad Sci. 2000;920:84-92 PMID: 11193180
  29. Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia.
    Am J Pathol. 2001 Feb;158(2):515-26 PMID: 11159188
  30. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease.
    J Neurosci. 2001 Jan 15;21(2):372-81 PMID: 11160418
  31. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.
    J Biol Chem. 2001 Jun 15;276(24):21562-70 PMID: 11279122
  32. Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides.
    Biochim Biophys Acta. 2001 Jul 27;1537(1):58-62 PMID: 11476963
  33. Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons.
    J Cell Biol. 2002 Feb 4;156(3):519-29 PMID: 11815632
  34. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
    Science. 2002 Jul 19;297(5580):353-6 PMID: 12130773
  35. Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease.
    Nat Rev Neurosci. 2002 Nov;3(11):862-72 PMID: 12415294
  36. Characterization of amyloid beta peptides from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein.
    J Neurochem. 2003 Feb;84(3):602-9 PMID: 12558980
  37. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7 PMID: 12634421
  38. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease.
    Neuron. 2004 Jan 8;41(1):27-33 PMID: 14715132
  39. Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6623-8 PMID: 15069204
Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
0896-6273
DOI
10.1016/j.neuron.2005.06.030
Published
2005-07-21
Pages
191-199
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC1373682
Subset
IM
Grants
NIA NIH HHS · R01 AG022595 · United States
NCI NIH HHS · R24 CA088325 · United States
NIA NIH HHS · R01 AG022595-02 · United States
NIA NIH HHS · R01 AG022595-01 · United States
NCI NIH HHS · CA88325 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2005.06.030 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2