Acta Neuropathologica

, Volume 83, Issue 1, pp 21–29

Deposition of β/A4 protein along neuronal plasma membranes in diffuse senile plaques

  • A. Probst
  • D. Langui
  • S. Ipsen
  • N. Robakis
  • J. Ulrich
Regular Papers


The origin of the extracellular β-amyloid protein (β/A4) found in senile plaques and the cellular mechanisms responsible for its deposition in cerebral tissues are still an unresolved issue in Alzheimer's disease. In this study we analyzed in detail the distribution of various epitopes of β/A4 in relation to local cellular elements in diffuse plaques of the hippocampal region. We also correlated our findings with the presence and distribution of non-β/A4 epitopes of the amyloid precursor protein (APP) and with synaptophysin immunoreactivity in the cortical neuropil. Discontinuous β/A4-immunoreactive deposits were found along dendrites, and around the soma of neurons included in the plaques. Furthermore, increased synaptophysin reactivity with slightly dilated synaptophysin-immunolabeled presynaptic terminals were found in diffuse plaques. APP epitopes could not be found in diffuse plaques. However, some of the APP antibodies, mainly those to the C-terminal portion of APP, and antibodies to β/A4 recognized clusters of flat vesicular profiles (0.6–1.4 μm in width and 2–3 μm in length) in the neuropil of cortical areas where plaques had developed. Our findings are compatible with a neuronal origin of β/A4 in diffuse plaques and with a primary release of β/A4 at synaptic sites along the immunostained neurites. They also suggest that diffuse plaques might be preceded by minute lesions of the neuropil where β/A4 is not yet released from the precursor molecule.

Key words

Diffuse plaques Dendrites Synapses β/A4 protein Amyloid precursor protein 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Allsop D, Haga SI, Haga C, Ikeda SI, Mann DMA, Ishii T (1989) Early senile plaques in Down's syndrome brains show a close relationship with cell bodies of neurons. Neuropathol Appl Neurobiol 15:531–542Google Scholar
  2. 2.
    Anderson JP, Refolo LM, Wallace W, Mehta P, Krishnamurthi M, Gotlib J, Bierer L, Haroutunian V, Perl D, Robakis NK (1989) Differential brain expression of the Alzheimer's amyloid precursor protein. EMBO J 8:3627–3632Google Scholar
  3. 3.
    Bahmanyar S, Higgins GA, Goldgaber D, Lewis DA, Morrison JH, Wilson MC, Shankar SK, Gajdusek DC (1987) Localization of β protein messenger RNA in brains from patients with Alzheimer's disease. Science 237:77–80Google Scholar
  4. 4.
    Blinzinger K, Kreuzberg G (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Z Zellforsch Mikrosk Anat 85:145–157Google Scholar
  5. 5.
    Brion JP, Couck AM, Bruce M, Anderton B, Flament-Durand J (1991) Synaptophysin and chromogranin A immunoreactivities in senile plaques of Alzheimers disease. Brain Res 539:143–150Google Scholar
  6. 6.
    Bugiani O, Giacone G, Verga L, Pollo B, Frangione B, Tagliavini F (1990) Alzheimer patients and Down patients: abnormal presynaptic terminals are related to cerebral preamyloid deposits. Neurosci Lett 119:56–59Google Scholar
  7. 7.
    Cork LC, Masters C, Beyreuther K, Price DL (1990) Development of senile plaques. Relationships of neuronal abnormalities and amyloid deposits. Am J Pathol 137:1383–1392Google Scholar
  8. 8.
    Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward P (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248:1122–1124Google Scholar
  9. 9.
    Glenner GG (1979) Congophilic microangiopathy in the pathogenesis of Alzheimer's syndrome (presenile dementia). Medical Hypotheses 5:1231–1236Google Scholar
  10. 10.
    Glenner GG, Wong CW (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890Google Scholar
  11. 11.
    Goedert M (1987) Neuronal localization of amyloid β protein precursor mRNA in normal human brain and in Alzheimer's disease. EMBO J 6:3627–3632Google Scholar
  12. 12.
    Higgins GA, Lewis DA, Bahmanyar S, Goldgaber DC, Gajdusek C, Young WG, Morrison JH, Wilson MD (1988) Differential regulation of amyloid-β-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer's disease. Proc Natl Acad Sci USA 85:1297–1301Google Scholar
  13. 13.
    Ikeda SI, Allsop D, Glenner GG (1989) Morphology and distribution of plaque and related deposits in the brain of Alzheimer's disease and control cases. An immunohistochemical study using amyloid β-protein antibody. Lab Invest 60:113–122Google Scholar
  14. 14.
    Jones DB (1957) Nephrotic glomerulonephritis. Am J Pathol 33:313–329Google Scholar
  15. 15.
    Khachaturian Z (1985) Diagnosis of Alzheimer's disease. Arch Neurol 52:1095–1105Google Scholar
  16. 16.
    Koo EK, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuter K, Fischer P, Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer's disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87:1561–1565Google Scholar
  17. 17.
    Mann DMA, Brown A, Prinja D, Davies CA, Landon M, Masters CL, Beyreuther K (1989) An analysis of the morphology of senile plaques in Down's syndrome patients of different ages using immunocytochemical and lectin histochemical methods. Neuropathol Appl Neurobiol 15:317–329Google Scholar
  18. 18.
    Masliah E, Terry RD, Mallory M, Alford M, Hansen LA (1990) Diffuse plaques do not accentuate synapse loss in Alzheimer's disease. Am J Pathol 137:1293–1297Google Scholar
  19. 19.
    Masters CL, Beyreuther K (1987) Neuronal origin of cerebral amyloidogenic proteins: their role in Alzheimer's disease and unconventional virus disease of the nervous system. In: Selective neuronal death. Ciba Found Symp 126:49–64Google Scholar
  20. 20.
    Masters CL, Mulhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4:2757–2763Google Scholar
  21. 21.
    Mattiace LA, Davies P, Yen SH, Dickson DW (1990) Microglia in cerebellar plaques in Alzheimer's disease. Acta Neuropathol 80:493–498Google Scholar
  22. 22.
    Miyakawa T, Shimoji A, Kuramoto R, Higuchi Y (1982) The relationship between senile plaques and cerebral blood vessels in Alzheimer's disease and senile dementia: morphological mechanism of senile plaque production. Virchows Arch [B] 40:121–129Google Scholar
  23. 23.
    Ogomori K, Kitamoto T, Tateishi J, Sato Y, Suetsugu M, Abe M (1989) β-Protein amyloid is widely distributed in the central nervous system of patients with Alzheimer's disease. Am J Pathol 134:243–251Google Scholar
  24. 24.
    Probst A, Brunnschweiler H, Lautenschlager C, Ulrich J, (1987) A special type of senile plaque, possibly an initial stage. Acta Neuropathol (Berl) 74:133–141Google Scholar
  25. 25.
    Rozemuller JM, Eikelenboom P, Stam FC, Beyreuther K, Masters CL (1989) A4 protein in Alzheimer's disease: primary and secondary cellular events in extracellular amyloid deposition. J Neuropathol Exp Neurology 48:674–691Google Scholar
  26. 26.
    Selkoe DJ (1989) Molecular pathology of amyloidogenic proteins and the role of vascular amyloidosis in Alzheimer's disease. Neurobiol Aging 10:387–395Google Scholar
  27. 27.
    Selkoe DJ, Abraham CR, Podlisny MB, Duffy LK (1986) Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer's disease. J Neurochem 146:1420–1434Google Scholar
  28. 28.
    Siman R, Card JP, Nelson RB, Davis LG (1989) Expression of β-amyloid precursor protein in reactive astrocytes following neuronal damage. Neuron 3:275–285Google Scholar
  29. 29.
    Soniat TTL (1941) Histogenesis of senile plaques. Arch Neurol 46:101–114Google Scholar
  30. 30.
    Streit WJ, Graeber MB, Kreutzberg GW (1988) Functional plasticity of microglia: a review. Glia 1:301–307Google Scholar
  31. 31.
    Tagliavini F, Giaccone G, Frangione B, Bugiani O (1988) Pre-amyloid deposits in the cerebral cortex of patients with Alzheimer's disease and non demented individuals. Neurosci Lett 93:191–196Google Scholar
  32. 32.
    Wiedenmann B, Franke WW (1985) Identification and localization of synaptophysin, an integral membrane glycoprotein of M r 38,000 characteristic of presynaptic vesicles. Cell 41:1017–1026Google Scholar
  33. 33.
    Wisniewski HM, Terry RD (1973) Re-examination of the pathogenesis of the senile plaque. Prog Neuropathol 2:1–26Google Scholar
  34. 34.
    Wisniewski HM, Bancher C, Barcikowska M, Wen GY, Curie J (1989) Spectrum of morphological appearances of amyloid deposits in Alzheimer's disease. Acta Neuropathol 78:337–347Google Scholar
  35. 35.
    Wisniewski HM, Wegiel J, Wang KC, Kujawa M, Lach B (1989) Ultrastructural studies of the cells forming amyloid fibers in classical plaques. Can J Neurol Sci 16:535–542Google Scholar
  36. 36.
    Yamaguchi H, Hirai S, Morimatsu M, Shoji M, Nakazato (1988) Diffuse type of senile plaques in the brains of Alzheimer-type dementia. Acta Neuropathol 77:113–119Google Scholar
  37. 37.
    Yamaguchi H, Nakazato Y, Hirai S, Shoji M, Harigaya Y (1989) Electron micrograph of diffuse plaques. Initial stage of senile plaque formation in the Alzheimer brain. Am J Pathol 135:593–597Google Scholar
  38. 38.
    Yamaguchi H, Nakazato Y, Hirai S, Shoji M (1990) Immunoelectron microscopic localization of amyloid β protein in the diffuse plaques of the Alzheimer-type dementia. Brain Res 508:320–324Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • A. Probst
    • 1
  • D. Langui
    • 1
  • S. Ipsen
    • 1
  • N. Robakis
    • 2
  • J. Ulrich
    • 1
  1. 1.Abteilung für NeuropathologieInstitut für PathologieBaselSwitzerland
  2. 2.Department of Psychiatry and Neurobiology CenterMount Sinai School of MedicineNew YorkUSA

Personalised recommendations