Accumulation of β-amyloid fibrils in pancreas of transgenic mice

Takeshi Kawarabayashi, Mikio Shoji, Masahiro Sato, Atsushi Sasaki, Libin Ho, Christopher B. Eckman, Christian Mihail Prada, Steven G. Younkin, Takashi Kobayashi, Norihiro Tada, Etsuro Matsubara, Tomomichi Iizuka, Yasuo Harigaya, Kazuhiro Kasai, Shunsaku Hirai

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Some forms of familial Alzheimer's disease are caused by mutations in the amyloid β protein precursor (βAPP), and there is excellent evidence that these mutations foster amyloid deposition by increasing secretion of total amyloid β protein (Aβ) or the highly amyloidogenic Aβ1-42 form. These observations provide a powerful rationale for developing an animal model of AD by generating transgenic mice in which cerebral amyloid deposition is induced by Aβ overproduction. To produce substantial Aβ in vivo, we generated mice expressing the transgene of signal peptide and 99 residues of carboxyl-terminal fragment (CTF) of βAPP under control of the cytomegalovirus enhancer/chicken β-actin promoter. The transgenic mRNA was detected in many tissues of these mice, bur the levels of transgenic mRNA, CTF, and Aβ did not correlate well indicating that tissue-specific posttranslational processing may play an important role in determining the amount of Aβ that accumulates in various tissues. Aβ was detected biochemically in brain, kidney, and pancreas with the largest amount present in pancreas. In transgenic plasma, there was a marked accumulation of human Aβ1-40 and Aβ1-42(43) to levels over 30-times those observed in normal human plasma. Thus, the transgenic mice produce and secrete considerable Aβ. Despite this increase in Aβ secretion and the elevated Aβ in brain, immunohistochemistry revealed no consistent cerebral Aβ deposition. In pancreas, however, intracellular Aβ deposits were detected immunohistochemically in acinar cells and interstitial macrophages, some of which showed severe degeneration. In addition, examination of these cells by immunoelectron microscopy revealed many putative amyloid fibrils (7-12 nm) that were stained by anti-Aβ antibodies. Overall, our findings indicate that tissue-specific posttranslational processing may play a pivotal role in Aβ production and amyloid fibril formation in vivo. By carefully analyzing the changes that occur in the transgenic mice described here as compared to the transgenic line that has recently been shown to form extracellular amyloid plaques in brain, it may be possible to gain considerable insight into the factors that determine the location and amount of Aβ that accumulates as amyloid.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalNeurobiology of aging
Volume17
Issue number2
DOIs
StatePublished - Jan 1 1996

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Keywords

  • Alzheimer's disease
  • Amyloid fibrils
  • Amyloid β protein
  • Amyloid β protein precursor
  • Carboxyl-terminal fragment
  • Pancreas
  • Transgenic mouse
  • β-actin promoter

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Kawarabayashi, T., Shoji, M., Sato, M., Sasaki, A., Ho, L., Eckman, C. B., Prada, C. M., Younkin, S. G., Kobayashi, T., Tada, N., Matsubara, E., Iizuka, T., Harigaya, Y., Kasai, K., & Hirai, S. (1996). Accumulation of β-amyloid fibrils in pancreas of transgenic mice. Neurobiology of aging, 17(2), 215-222. https://doi.org/10.1016/0197-4580(95)02061-6