The role of the carboxyl-terminal fragments of amyloid precursor protein in Alzheimer's disease

D. K. Lahiri, G. J. Kotwal, M. R. Farlow, A. Sima, W. Kupsky, F. H. Sarkar, K. Sambamurti

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Two major pathological hallmarks of Alzheimer's disease (AD) are the senile plaques that are primarily composed of amyloid β-peptide (Aβ) and neurofibrillary tangles consisting of tau aggregates. Aβ is generated proteolytically from a family of Aβ-containing precursor proteins (APP; 695-770 amino acid) by secretase enzymes to different specific carboxyl-terminal fragments (CTFs). Herein we examined APP and its products in autopsied brain sections from 10 AD and 10 non-AD control subjects immunochemically using an antibody that was raised against APP751-770 residue (O443). The O443 antibody was initially characterized by Western blot analysis and immunoprecipitation. In this study, we used this antibody for immunohistochemical analysis to determine the distribution of APP and its CTF species. In 10 brain regions showing different levels of plaques and tangles, antibody O443 stained the perinuclear region of the nucleus, plaques, and neurites. Tangle-bearing neurons also appeared to stain with the antibody, suggesting that these dysfunctional neurons continue to synthesize APP/CTF. Alternatively, the normally short-lived APP/CTF can be stabilized and persist in these neurons. Taken together, these results suggest that, in addition to the widely believed role of Aβ, CTFs may play a key role in the pathogenesis of AD. Studying their localization and biogenesis may reveal the biological activities of CTFs of APP. The present study may pave the way for possible antiamyloidogenic therapy in the treatment of AD.

Original languageEnglish (US)
Pages (from-to)334-339
Number of pages6
JournalAnnals of the New York Academy of Sciences
Volume973
DOIs
StatePublished - Jan 1 2002

Keywords

  • Alzheimer's disease
  • Amyloid β-peptide
  • Amyloid precursor protein
  • Carboxyl-truncated fragments
  • Neurofibrillary tangles

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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