Skip to main content
SpringerLink
Log in

Neurodegenerative Alzheimer-like Pathology in PDAPP 717V → F Transgenic Mice

  • Conference paper
Connections, Cognition and Alzheimer’s Disease

Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

Summary

Predominant pathological hallmarks of Alzheimer’s (AD) include the region-specific deposition of β amyloid (Aβ) plaques, vascular amyloidosis, and a number of distinct neurodegenerative changes. These involve the formation of dystrophic neurites and neuritic plaques, cytoskeletal alterations, and synaptic and neuronal loss. Astrocytosis and microgliosis are also evident in affected brain regions. Transgenic (tg) mice overexpressing a mutant form of the β-amyloid precursor protein (APP 717 V→ F) develop several of these pathologies in an age- and region-dependent manner similar to AD. Aβ plaques in the transgenic mouse share many of the tinctorial and immunohistochemical properties of AD plaques, including the relative distribution of AβX-40 and AβX-42 isoforms and the presence of other plaque-associated proteins. Initial findings using immunoassays specific to unique forms of APP and Aβ suggest that APP levels do not dramatically change with increasing age in the mouse brains, and that region-specific variations in APP metabolism, local factors or deficits in distinct populations of neurons account for the deposition of brain Aβ. The PDAPP mouse is a relevant and efficient model system to identify mechanistic properties of the disease process and offers novel opportunities to test potential therapeutics.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abraham CR, Selkoe DJ, Potter H (1988) Immunohistochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin inhibitor in the brain amyloid deposits of Alzheimer’s disease. Cell 52: 487 – 501

    Article  PubMed  CAS  Google Scholar 

  • Akiyama H, McGeer PL (1990) Brain microglia constitutively express β-2 integrins. J Neuroimmunol 30: 81 – 93

    Article  PubMed  CAS  Google Scholar 

  • Arai H, Lee VM, Otvos LJr, Greenberg BD, Lowery DE, Sharma SK, Schmidt ML, Trojanowski JQ (1990) Defined neurofilament, tau, and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer plaques. Proc Natl Acad Sci USA 87: 2249–2253

    Article  PubMed  CAS  Google Scholar 

  • Asian PS, Davis KL (1994) Inflammatory mechanisms in Alzheimer’s disease: implications for therapy. Am J Psych 151: 1105 – 1113

    Google Scholar 

  • Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16: 271 – 278

    Article  PubMed  CAS  Google Scholar 

  • Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeletal changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropath 87: 554 – 567

    Article  PubMed  CAS  Google Scholar 

  • Cairns NJ, Chadwick A, Luthert PJ, Lantos PL (1992) Astrocytosis, beta A4-protein and paired helical filament formation in Alzheimer’s disease. J Neurol Sci 112: 68 – 75

    Article  PubMed  CAS  Google Scholar 

  • Caporasco L, Gandy SE, Buxbaum JD, Ramabhadran TV, Greengard P (1992) Protein phosphorylation regulates secretion of Alzheimer’s β/A4 amyloid precursor protein. Proc Natl Acad Sci USA 89, 3055 – 3059

    Article  Google Scholar 

  • Cataldo AM, Hamilton DJ, Nixon RA (1994) Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease. Brain Res 640: 68 – 80

    Article  PubMed  CAS  Google Scholar 

  • Cotman CW, Cummings BJ, Whitson JS (1991) The role of misdirected plasticity in plaque biogenesis and Alzheimer’s disease pathology. In: Growth factors and Alzheimer’s disease. Hefti F, Brachet P, Will B, Christen Y (eds) Alzheimer’s disease and related conditions. Springer-Verlag, Heidelberg, pp. 222 – 233

    Google Scholar 

  • Cummings BJ, Su JH, Cotman CW, White R, Russell MJ (1993) Beta-amyloid accumulation in aged canine brain: a model of early plaque formation in Alzheimer’s disease. Neurobiol Aging 14: 547 – 560

    Article  PubMed  CAS  Google Scholar 

  • Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248: 1122 – 1128

    Article  PubMed  CAS  Google Scholar 

  • Fredrickson RC (1992) Astroglia in Alzheimer’s disease. Neurobiol Aging 13: 239 – 253

    Article  Google Scholar 

  • Fukumoto H, Asami-Odaka A, Suzuki N, Shimada H, Ihara Y, Iwatsubo T (1996) Amyloid β protein in normal aging has the same characteristics as that in Alzheimer’s disease. Am J Pathol 148: 259 – 265

    PubMed  CAS  Google Scholar 

  • Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie R, Guido T, Hagopian S, Johnson-Wood K, Khan I, Lee M, Leibowitz P, Liebergurb I, Little S, Masliah E, McConlogue L, Montoya Azvala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995) Development of neuropathology similar to Alzheimer’s disease in transgenic mice overexpressing the 717V→F β-amyloid precursor protein. Nature 373: 523 – 527

    Article  PubMed  CAS  Google Scholar 

  • Goedert M, Jakes R, Crowther RA, Six J, Lubke U, Vandermeeren M, Cras P, Trojanowski JQ, Lee VM (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer’s disease recapitulates phosphorylation during development. Proc Natl Acad Sci USA 90: 5066 – 5070

    Article  PubMed  CAS  Google Scholar 

  • Heinonen O, Soininen H, Sorvari H, Kosunen O, Paljarvi L, Koivisto E, Riekkinen PJ (1995) Loss of synaptin-like immunoreactivitiy in the hippocampal formation as an early phenomenon in Alzheimer’s disease. Neuroscience 64: 375 – 384

    Article  PubMed  CAS  Google Scholar 

  • Higgins LS, Holtzman DM, Rabin J, Mobley WC, Cordell B (1994) Transgenic mouse brain histophathology resembles early Alzheimer’s disease. Ann Neurol 35: 598 – 607

    Article  PubMed  CAS  Google Scholar 

  • Honer WG, Dickson DW, Gleeson J, Davies P (1992) Regional synaptic pathology in Alzheimer’s disease. Neurobiol Aging 13: 375 – 382

    Article  PubMed  CAS  Google Scholar 

  • Hyman BT (1992) Down Syndrome and Alzheimer’s disease: Progress in clinical and biological research. Prog Clin Biol Res 379: 123 – 142

    PubMed  CAS  Google Scholar 

  • Hyman BT, Van Hoesen BW, Damasio AR (1990) Memory-related neural systems in Alzheimer’s disease: An anatomical study. Neurology 40: 1721 – 1730

    PubMed  CAS  Google Scholar 

  • Iwatsubo T, Mann DMA, Odaka A, Suzuki N, Ihara Y (1995) Amyloid β protein (Aβ) deposition: Aβ 42 (43) precedes Aβ40 in Down Syndrome. Ann Neurol 37: 294 – 299

    Article  PubMed  CAS  Google Scholar 

  • Joachim C, Games D, Morris J, Ward P, Frenkel D, Selkoe D (1991) Antibodies to non-beta regions of the beta-amyloid precursor protein defect a subset of senile plaques. Am J Pathol 138: 373 – 384

    PubMed  CAS  Google Scholar 

  • Lemere CA, Blusztajn Y, Yamaguchi T, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid β-peptides and Apo E in Down syndrome: Implications for initial events in amyloid plaque formation. Neurobiol Disease 3: 16 – 32

    Article  CAS  Google Scholar 

  • Mann DA (1988) The pathological association between Down Syndrome and Alzheimer’s disease. Mech Aging Develop 43: 99 – 136

    Article  CAS  Google Scholar 

  • Mann DMA (1989) Cerebral amyloidosis, aging and Alzheimer’s disease: A contribution of studies from Down’s Syndrome. Neurobiol Aging 10: 397 – 399

    Article  PubMed  CAS  Google Scholar 

  • Mann DMA (1994) Alzheimer’s disease: Progress in pathological and aetiological aspects. Res Gerontol 4: 43 – 60

    Article  Google Scholar 

  • McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglial in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79: 195 – 200

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Miller A, Terry RD (1993a) The synaptic organization of the neocortex in Alzheimers disease. Medical Hypothesis 41: 334 – 340

    Article  CAS  Google Scholar 

  • Masliah E, Mallory M, Deerink T, DeTeresa R, Lamont S, Miller A, Terry R, Carragher B, Ellisman M (1993b) Re-evaluation of the structural organization of neuritic plaques in Alzheimer’s disease. J Neuropathol Exp Neurol 52: 619 – 632

    Article  CAS  Google Scholar 

  • Masliah E, Mallory M, Hansen L, Alford M, DeTeresa R, Terry R (1993c) An antibody against phos-phorylated neurofilaments identifies a subset of damaged association axons in Alzheimer’s disease. Am J Pathol 142: 871 – 882

    PubMed  CAS  Google Scholar 

  • Murrell J, FarlowM, Ghetti B, Benson M (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254: 97 – 99

    Article  PubMed  CAS  Google Scholar 

  • Oltersdorf T, Fritz LC, Schenk DB, Lieberburg I, Johnson-Wood K, Beattie EC, Ward PJ, Blacher RW, Dovey HF, Sinha S (1989) The secreted form of the Alzheimer’s amyloid precursor protein with the Kunitz domain is Protease Nexin II. Nature 341: 144 – 147

    Article  PubMed  CAS  Google Scholar 

  • Perlmutter LS, Scott SA, Chui HC (1991) The role of microglia in the cortical neuropathology of Alzheimer disease. Bull Clin Neurosci 56: 120 – 130

    Google Scholar 

  • Pike CJ, Cummings BJ, Cotman CW (1995) Early association of reactive astrocytes with senile plaques in Alzheimer’s disease. Exper Neurol 132: 172 – 179

    Article  CAS  Google Scholar 

  • Price DL, Martin LJ, Sisodia SS, Wagner MV, Koo EH, Walker LC, Koliatos VE, Cork LC (1991) Aged non-human primates: An animal model of age-associated neurodegenerative disease. Brain Pathol 1: 287 – 296

    Article  PubMed  CAS  Google Scholar 

  • Rockenstein EM, McConlogue L, Tan H, Power M, Masliah E, Mucke L (1995) Levels and alternative splicing of amyloid β protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J Biol Chem 270: 28257 – 28267

    Article  PubMed  CAS  Google Scholar 

  • Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune-system-associated antigens by cells of the human central nervous system: Realationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9: 339 – 349

    Article  PubMed  CAS  Google Scholar 

  • Selkoe D (1991) The molecular pathology of Alzheimer’s disease. Neuron 6: 487–498

    Article  CAS  Google Scholar 

  • Selkoe DJ, Bell DS, PodlinskyMB, Price DL, Cork LC (1987) Conservation of brain amyloid in aged mammals and humans with Alzheimer’s disease. Science 235: 873 – 877

    Google Scholar 

  • Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert F, Selkow D, Lieberburg I, Schenk D (1992) Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 359: 325 – 327

    Article  PubMed  CAS  Google Scholar 

  • Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL, Bryant K, Fritz LD, Galasko D, Thal LJ, Lieberburg I, Schenk DB (1993) Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide. Nature 361: 260 – 263

    Article  PubMed  CAS  Google Scholar 

  • Snow AD, Mar H, Nochlin D, Kimata K, Kato M, Suzuki S, Hassell J, Wight TN (1988) The presence of heparin sulfate proteoglycans in the neuritic plaques and congophilic angiopathy of Alzheimer’s disease. Am J Pathol 133: 456 – 463

    PubMed  CAS  Google Scholar 

  • Su JH, Cummings BJ, Cotman CW (1994) Early phosphorylation of tau in Alzheimer’s disease occurs at Ser-202 and is preferentially located within neurites. Neuro Report 5: 2358 – 2362

    CAS  Google Scholar 

  • Takahashi H, Kurashima C, Utuyama M, Hirokawa K (1990) Immunohistological study of senile brains using a monoclonal antibody recognizing beta amyloid precursor protein, significance of granular deposits in relation with senile plaques. Acta Neuropathol 80: 260 – 265

    Article  PubMed  CAS  Google Scholar 

  • Terry RD, Masliah E, Hansen LA (1994) Structural basis of the cognitive alterations in Alzheimer’s disease. In: Terry RD, Katzman R, Bick KL (eds). Alzheimer’s disease. Raven Press, New York pp. 179 – 196

    Google Scholar 

  • Van Eldik LJ, Griffin WS (1994) SlOO beta expression in Alzheimer’s disease: relation to neuropathology in brain regions. Biochim Biophys Acta 1223: 398 – 403

    Article  Google Scholar 

  • Van Hoesen GW, Hyman BT (1990) Hippocampal formation: Anatomy and the patterns of pathology in Alzheimer’s disease. Prog Brain Res 83: 445 – 457

    Article  PubMed  Google Scholar 

  • Vickers JC, Riederer BM, Marugg RA, Buee-Scherrer V, Buee L, Delacourte A, Morrison JH (1994) Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer’s disease. Neuroscience 62: 1 – 13

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski HM, Bancher C, Barcikowska M, Wen GY, Currie J (1989) Spectrum of morphological appearance of amyloid deposits in Alzheimer’s disease. Acta Neurophathol 78: 337 – 347

    Article  CAS  Google Scholar 

  • Yamaguchi H, Harai S, Morimatsu M, Shoji M, Ihara Y (1988) A variety of cerebral amyloid deposits in the brains of Alzheimer-type dementia demonstrated by β protein immunostaining. Acta Neuropathol 541 – 549

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Athena Neurosciences, 800 Gateway Blvd, South San Francisco, California, 94002, USA

    D. Games

Authors
  1. D. Games
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Masliah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Johnson-Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Schenk
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Nuerology Service, Massachusetts General Hospital, Fruit Street, 02114, Boston, MA, USA

    B. T. Hayman M.D., Ph.D.

  2. Laboratoire de Neuropathologie R. Escourolle, Hôpital de La Salpêtrière, Blvd. de l’Hôpital, 75651, Paris Cedex 16, France

    C. Duyckaerts M.D., Ph.D.

  3. Fondation IPSEN, 24, rue Erlanger, 75651, Paris Cedex 16, France

    Y. Christen Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1997 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Games, D., Masliah, E., Lee, M., Johnson-Wood, K., Schenk, D. (1997). Neurodegenerative Alzheimer-like Pathology in PDAPP 717V → F Transgenic Mice. In: Hayman, B.T., Duyckaerts, C., Christen, Y. (eds) Connections, Cognition and Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60680-9_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-60680-9_8

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64504-4

  • Online ISBN: 978-3-642-60680-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation