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PMID: 15452128 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Altered amyloid-beta metabolism and deposition in genomic-based beta-secretase transgenic mice.

The Journal of biological chemistry ·Vol. 279 ·No. 50 ·2004-12-10 ·Pages 52535-42

Chiocco MJ, Kulnane LS, Younkin L, Younkin S, Evin G, Lamb BT

Abstract

Amyloid-beta (Abeta) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by beta-secretase followed by gamma-secretase cleavage. Identification of the primary beta-secretase gene, BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Abeta metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating beta-secretase expression and activity alters APP processing and Abeta metabolism in vivo. Genomic-based BACE1 transgenic mice were generated that overexpress human BACE1 mRNA and protein. The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing both BACE1 and APP show specific alterations in APP processing and age-dependent Abeta deposition. We observed elevated levels of Abeta isoforms as well as significant increases of Abeta deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for beta-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation of BACE1 activity may play a significant role in AD pathogenesis in vivo.

MeSH Terms
Alzheimer Disease/metabolism Amyloid Precursor Protein Secretases Amyloid beta-Peptides/metabolism Amyloid beta-Protein Precursor/genetics,metabolism Animals Aspartic Acid Endopeptidases/genetics,metabolism Endopeptidases Female Gene Expression Genomics Humans Immunohistochemistry Male Mice Mice, Inbred C57BL Mice, Transgenic Protein Processing, Post-Translational RNA, Messenger/genetics,metabolism
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor RNA, Messenger Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Chiocco Matthew J
Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Kulnane Laura Shapiro
Younkin Linda
Younkin Steve
Evin Geneviève
Lamb Bruce T
References (50)
50 references, click to expand
  1. Mutations in the open reading frame of the beta-site APP cleaving enzyme (BACE) locus are not a common cause of Alzheimer's disease.
    Neurogenetics. 2001 Oct;3(4):203-6 PMID: 11714100
  2. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP.
    Nature. 2001 Dec 6;414(6864):643-8 PMID: 11740561
  3. Neuropathological characterization of mutant amyloid precursor protein yeast artificial chromosome transgenic mice.
    Neurobiol Dis. 2001 Dec;8(6):982-92 PMID: 11741394
  4. Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid.
    J Neurochem. 2002 Mar;80(5):799-806 PMID: 11948243
  5. Localization of beta-secretase memapsin 2 in the brain of Alzheimer's patients and normal aged controls.
    Exp Neurol. 2002 May;175(1):10-22 PMID: 12009756
  6. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease.
    Ann Neurol. 2002 Jun;51(6):783-6 PMID: 12112088
  7. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10843-8 PMID: 12145324
  8. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease.
    Arch Neurol. 2002 Sep;59(9):1381-9 PMID: 12223024
  9. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease.
    Nat Med. 2003 Jan;9(1):3-4 PMID: 12514700
  10. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
    Science. 1999 Oct 22;286(5440):735-41 PMID: 10531052
  11. A genetic dichotomy model for the inheritance of Alzheimer's disease and common age-related disorders.
    J Clin Invest. 1999 Nov;104(9):1175-9 PMID: 10545516
  12. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity.
    Nature. 1999 Dec 2;402(6761):533-7 PMID: 10591213
  13. Purification and cloning of amyloid precursor protein beta-secretase from human brain.
    Nature. 1999 Dec 2;402(6761):537-40 PMID: 10591214
  14. Identification of a novel aspartic protease (Asp 2) as beta-secretase.
    Mol Cell Neurosci. 1999 Dec;14(6):419-27 PMID: 10656250
  15. Coordinated expression of beta-amyloid precursor protein and the putative beta-secretase BACE and alpha-secretase ADAM10 in mouse and human brain.
    J Neurochem. 2000 Nov;75(5):2133-43 PMID: 11032903
  16. beta-site APP cleaving enzyme mRNA expression in APP transgenic mice: anatomical overlap with transgene expression and static levels with aging.
    Am J Pathol. 2001 Jan;158(1):173-7 PMID: 11141490
  17. Olfactory centres in Alzheimer's disease: olfactory bulb is involved in early Braak's stages.
    Neuroreport. 2001 Feb 12,;12(2):285-8 PMID: 11209936
  18. 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
  19. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation.
    Nat Neurosci. 2001 Mar;4(3):231-2 PMID: 11224535
  20. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons.
    Nat Neurosci. 2001 Mar;4(3):233-4 PMID: 11224536
  21. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.
    Hum Mol Genet. 2001 Jun 1;10(12):1317-24 PMID: 11406613
  22. Association studies using novel polymorphisms in BACE1 and BACE2.
    Neuroreport. 2001 Jul 3;12(9):1799-802 PMID: 11435901
  23. The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate.
    J Biol Chem. 2001 Sep 28;276(39):36788-96 PMID: 11466313
  24. The association of beta-site APP cleaving enzyme (BACE) C786G polymorphism with Alzheimer's disease.
    Brain Res. 2003 Jan 24;961(1):88-91 PMID: 12535780
  25. Early olfactory involvement in Alzheimer's disease.
    Can J Neurol Sci. 2003 Feb;30(1):20-5 PMID: 12619779
  26. Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers.
    Am J Med Genet B Neuropsychiatr Genet. 2003 May 15;119B(1):44-7 PMID: 12707937
  27. Quantification and distribution of beta-secretase alternative splice variants in the rat and human brain.
    Brain Res Mol Brain Res. 2003 Jul 4;115(1):63-8 PMID: 12824056
  28. Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes.
    J Cell Sci. 2003 Aug 15;116(Pt 16):3339-46 PMID: 12829747
  29. Alterations in beta-amyloid production and deposition in brain regions of two transgenic models.
    Neurobiol Aging. 2003 Sep;24(5):645-53 PMID: 12885572
  30. Association study between Alzheimer's disease and genes involved in Abeta biosynthesis, aggregation and degradation: suggestive results with BACE1.
    J Neurol. 2003 Aug;250(8):956-61 PMID: 12928915
  31. The beta-amyloid-related proteins presenilin 1 and BACE1 are axonally transported to nerve terminals in the brain.
    Exp Neurol. 2003 Dec;184(2):1053-7 PMID: 14769400
  32. Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology.
    J Neural Transm (Vienna). 2004 Mar;111(3):413-25 PMID: 14991462
  33. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients.
    Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3632-7 PMID: 14978286
  34. Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders.
    Ageing Res Rev. 2004 Apr;3(2):215-32 PMID: 15177056
  35. A simple salting out procedure for extracting DNA from human nucleated cells.
    Nucleic Acids Res. 1988 Feb 11;16(3):1215 PMID: 3344216
  36. The nature and course of olfactory deficits in Alzheimer's disease.
    Am J Psychiatry. 1991 Mar;148(3):357-60 PMID: 1992839
  37. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production.
    Nature. 1992 Dec 17;360(6405):672-4 PMID: 1465129
  38. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.
    Nat Genet. 1992 Aug;1(5):345-7 PMID: 1302033
  39. Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected].
    Nat Genet. 1993 Sep;5(1):22-30 PMID: 8220418
  40. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants.
    Science. 1994 May 27;264(5163):1336-40 PMID: 8191290
  41. Olfactory identification deficits in relatives of Alzheimer's disease patients.
    Biol Psychiatry. 1996 Mar 1;39(5):375-7 PMID: 8704071
  42. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.
    Science. 1996 Oct 4;274(5284):99-102 PMID: 8810256
  43. Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease.
    Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1550-5 PMID: 9037091
  44. Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.
    Hum Mol Genet. 1997 Sep;6(9):1535-41 PMID: 9285791
  45. Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome.
    Nat Biotechnol. 1997 Sep;15(9):859-65 PMID: 9306400
  46. Frequency of stages of Alzheimer-related lesions in different age categories.
    Neurobiol Aging. 1997 Jul-Aug;18(4):351-7 PMID: 9330961
  47. Translating cell biology into therapeutic advances in Alzheimer's disease.
    Nature. 1999 Jun 24;399(6738 Suppl):A23-31 PMID: 10392577
  48. Alzheimer pathology disorganizes cortico-cortical circuitry: direct evidence from a transgenic animal model.
    Neurobiol Dis. 2004 Jun;16(1):41-7 PMID: 15207260
  49. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.
    Biochem Biophys Res Commun. 1984 May 16;120(3):885-90 PMID: 6375662
  50. Presence of both odor identification and detection deficits in Alzheimer's disease.
    Brain Res Bull. 1987 May;18(5):597-600 PMID: 3607528
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M409680200
Published
2004-12-10
Epub
2004-00-27
Pages
52535-42
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2659546
Subset
IM
Grants
NCI NIH HHS · P30 CA043703 · United States
NIA NIH HHS · R01 AG023012-01A1 · United States
NCI NIH HHS · CA43703 · United States
NIA NIH HHS · AG08012 · United States
NIA NIH HHS · R01 AG023012 · United States
NIA NIH HHS · P50 AG008012 · United States
NIGMS NIH HHS · GM08056-21 · United States
NIA NIH HHS · AG14451 · United States
External Links
PubMed source DOI: 10.1074/jbc.M409680200 PMC Full Text View journal details
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