Acta Neuropathologica

, Volume 108, Issue 5, pp 435–442 | Cite as

Exclusive association and simultaneous appearance of congophilic plaques and AT8-positive dystrophic neurites in Tg2576 mice suggest a mechanism of senile plaque formation and progression of neuritic dystrophy in Alzheimer’s disease

  • Kyoko Noda-Saita
  • Kazuhiro Terai
  • Akihiko Iwai
  • Mina Tsukamoto
  • Yoshitsugu Shitaka
  • Shigeki Kawabata
  • Masamichi Okada
  • Tokio Yamaguchi
Regular Paper
First Online:
Received:
Revised:
Accepted:

Abstracts

Progression of neuritic dystrophy is a histological hallmark of Alzheimer’s disease (AD) in addition to amyloid deposition and neurofibrillary tangle formation. Dystrophic neurites (DNs) are abnormal neurites, and are closely associated with amyloid deposits. To clarify the process of DN formation, we immunohistochemically investigated phosphorylated tau (AT8 and Ser396)-positive DNs and plaques in Tg2576 mice overexpressing human β-amyloid precursor protein (APP) with the Swedish type mutation (K670N/M671L). AT8-positive DNs were exclusively associated with the Congo red-positive plaques examined, and all Aβ1–40-positive plaques appeared to be associated with AT8-positive DNs, whereas there were no AT8-positive DNs with Aβ1–42-positive/Aβ1–40-negative plaques. Since we have previously shown that Aβ1–42-positive plaque precede Aβ1–40 deposition, the appearance of congophilic structures is also late. Quantitative analyses were performed on AT8-positive DNs that were associated with congophilic plaques in the cerebral cortex and hippocampus (more than 1,000 plaques). The number of congophilic plaques increased dramatically with age. The area of DNs in the cerebral cortex and hippocampus increased 120- and 60-fold from 11–13 to 20.5 months of age, respectively. Interestingly, the mean ratio of DN area to congophilic plaque area in every plaque was unchanged, approximately 10%, through the ages examined. The mean plaque size was stable with age in both the cortex and hippocampus. These data suggest that the formation of AT8-positive DNs is simultaneous with Congo red-positive plaque development, and that the event may be closely related in the pathological progression of AD.

Keywords

Alzheimer’s disease Dystrophic neurite Congophilic plaque Tau Quantitative analysis 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Armstrong RA (1998) β-amyloid plaques: stages in life history or independent origin? Dement Geriatr Cogn Disord 9:227–238PubMedGoogle Scholar
  2. 2.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedGoogle Scholar
  3. 3.
    Braak H, Braak E (1997) Staging of Alzheimer-related cortical destruction. Int Psychogeriatr 9:257–261CrossRefGoogle Scholar
  4. 4.
    Carlson GA, Borchelt DR, Dake A, Turner S, Danielson V, Coffin JD, Eckman C, Meiners J, Nilsen SP, Younkin SG, Hsiao KK (1997) Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum Mol Genet 6:1951–1959PubMedGoogle Scholar
  5. 5.
    Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2:271–276PubMedGoogle Scholar
  6. 6.
    Christie RH, Bacskai BJ, Zipfel WR, Williams RM, Kajdasz ST, Webb WW, Hyman BT (2001) Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy. J Neurosci 21:858–864Google Scholar
  7. 7.
    Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH (1988) Alzheimer’s disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol 132:86–101PubMedGoogle Scholar
  8. 8.
    Fraser PE, Levesque L, McLachlan DR (1993) Biochemistry of Alzheimer’s disease amyloid plaques. Clin Biochem 26:339–349PubMedGoogle Scholar
  9. 9.
    Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, Cole GM (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152:307–317PubMedGoogle Scholar
  10. 10.
    Fukumoto H, Asami-Odaka A, Suzuki N, Iwatsubo T (1996) Association of Aβ 40-positive senile plaques with microglial cells in the brains of patients with Alzheimer’s disease and in non-demented aged individuals. Neurodegeneration 5:13–17PubMedGoogle Scholar
  11. 11.
    Fukumoto H, Asami-Odaka A, Suzuki N, Shimada H, Ihara Y, Iwatsubo T (1996) Amyloid β protein deposition in normal aging has the same characteristics as that in Alzheimer’s disease. Predominance of Aβ 42(43) and association of Aβ 40 with cored plaques. Am J Pathol 148:259–265PubMedGoogle Scholar
  12. 12.
    Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373:523–527CrossRefPubMedGoogle Scholar
  13. 13.
    Greenberg SG, Davies P (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci USA 87:5827–5831PubMedGoogle Scholar
  14. 14.
    Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedGoogle Scholar
  15. 15.
    Ikeda K, Haga C, Kosaka K, Oyanagi S (1989) Senile plaque-like structures: observation of a probably unknown type of senile plaque by periodic-acid methenamine silver (PAM) electron microscopy. Acta Neuropathol 78:137–142PubMedGoogle Scholar
  16. 16.
    Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT (1997) APPSw transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol 56:965–973Google Scholar
  17. 17.
    Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of Aβ 42(43) and Aβ 40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ 42(43). Neuron 13:45–53CrossRefPubMedGoogle Scholar
  18. 18.
    Lorenzo A, Yankner BA (1994) β-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci USA 91:12243–12247PubMedGoogle Scholar
  19. 19.
    Mann DM, Iwatsubo T, Ihara Y, Cairns NJ, Lantos PL, Bogdanovic N, Lannfelt L, Winblad B, Maat-Schieman ML, Rossor MN (1996) Predominant deposition of amyloid-β 42(43) in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am J Pathol 148:1257–1266PubMedGoogle Scholar
  20. 20.
    Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (1996) Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer’s disease. J Neurosci 16:5795–5811Google Scholar
  21. 21.
    McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 21:195–218CrossRefPubMedGoogle Scholar
  22. 22.
    McKee AC, Kosik KS, Kowall NW (1991) Neuritic pathology and dementia in Alzheimer’s disease. Ann Neurol 30:156–165PubMedGoogle Scholar
  23. 23.
    Mehta PD, Dalton AJ, Mehta SP, Kim KS, Wisniewski HM, Aisen PS (1997) Plasma amyloid β1–42 levels are increased in Down’s syndrome but not in Alzheimer’s disease. Ann Neurol 42 (Suppl M29):400Google Scholar
  24. 24.
    Mehta PD, Dalton AJ, Mehta SP, Kim KS, Sersen EA, Wisniewski HM (1998) Increased plasma amyloid β protein 1–42 levels in Down syndrome. Neurosci Lett 241:13–16CrossRefPubMedGoogle Scholar
  25. 25.
    Metsaars WP, Hauw JJ, Welsem ME van, Duyckaerts C (2003) A grading system of Alzheimer disease lesions in neocortical areas. Neurobiol Aging 24:563–572CrossRefPubMedGoogle Scholar
  26. 26.
    Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Belle G van, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  27. 27.
    Onorato M, Mulvihill P, Connolly J, Galloway P, Whitehouse P, Perry G (1989) Alteration of neuritic cytoarchitecture in Alzheimer disease. Prog Clin Biol Res 317:781–789PubMedGoogle Scholar
  28. 28.
    Pappolla MA, Chyan YJ, Omar RA, Hsiao K, Perry G, Smith MA, Bozner P (1998) Evidence of oxidative stress and in vivo neurotoxicity of β-amyloid in a transgenic mouse model of Alzheimer’s disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol 152:871–877PubMedGoogle Scholar
  29. 29.
    Price DL, Tanzi RE, Borchelt DR, Sisodia SS (1998) Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 32:461–493CrossRefPubMedGoogle Scholar
  30. 30.
    Selkoe DJ (1994) Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurol 53:438–447Google Scholar
  31. 31.
    Selkoe DJ (1998) The cell biology of β-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 8:447–453Google Scholar
  32. 32.
    Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G (1998) Amyloid-β deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215Google Scholar
  33. 33.
    Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292CrossRefPubMedGoogle Scholar
  34. 34.
    Styren SD, Hamilton RL, Styren GC, Klunk WE (2000) X-34, a fluorescent derivative of Congo red: a novel histochemical stain for Alzheimer’s disease pathology. J Histochem Cytochem 48:1223–1232PubMedGoogle Scholar
  35. 35.
    Su JH, Cummings BJ, Cotman CW (1998) Plaque biogenesis in brain aging and Alzheimer’s disease. II. Progressive transformation and developmental sequence of dystrophic neurites. Acta Neuropathol 96:463–471CrossRefPubMedGoogle Scholar
  36. 36.
    Takeuchi A, Irizarry MC, Duff K, Saido TC, Hsiao Ashe K, Hasegawa M, Mann DM, Hyman BT, Iwatsubo T (2000) Age-related amyloid β deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid β precursor protein Swedish mutant is not associated with global neuronal loss. Am J Pathol 157:331–339PubMedGoogle Scholar
  37. 37.
    Terai K, Iwai A, Kawabata S, Sasamata M, Miyata K, Yamaguchi T (2001) Apolipoprotein E deposition and astrogliosis are associated with maturation of β-amyloid plaques in βAPPswe transgenic mouse: implications for the pathogenesis of Alzheimer’s disease. Brain Res 900:48–56CrossRefPubMedGoogle Scholar
  38. 38.
    Terai K, Iwai A, Kawabata S, Tasaki Y, Watanabe T, Miyata K, Yamaguchi T (2001) β-amyloid deposits in transgenic mice expressing human β-amyloid precursor protein have the same characteristics as those in Alzheimer’s disease. Neuroscience 104:299–310CrossRefPubMedGoogle Scholar
  39. 39.
    Tomidokoro Y, Ishiguro K, Harigaya Y, Matsubara E, Ikeda M, Park JM, Yasutake K, Kawarabayashi T, Okamoto K, Shoji M (2001) Aβ amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice. Neurosci Lett 299:169–172CrossRefPubMedGoogle Scholar
  40. 40.
    Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH (2002) The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 22:1858–1867Google Scholar
  41. 41.
    Yilmazer-Hanke DM (1998) Pathogenesis of Alzheimer-related neuritic plaques: AT8 immunoreactive dystrophic neurites precede argyrophilic neurites in plaques of the entorhinal region, hippocampal formation, and amygdala. Clin Neuropathol 17:194–198PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Kyoko Noda-Saita
    • 1
  • Kazuhiro Terai
    • 1
  • Akihiko Iwai
    • 1
  • Mina Tsukamoto
    • 1
  • Yoshitsugu Shitaka
    • 1
  • Shigeki Kawabata
    • 2
  • Masamichi Okada
    • 1
  • Tokio Yamaguchi
    • 1
  1. 1.Neuroscience ResearchYamanouchi Pharmaceutical Company LimitedIbarakiJapan
  2. 2.Molecular Medicine ResearchYamanouchi Pharmaceutical Company LimitedIbarakiJapan

Personalised recommendations