Production of Amyloid β Protein from Normal Amyloid β‐Protein Precursor (βAPP) and the Mutated βAPPS Linked to Familial Alzheimer's Disease

TODD E. GOLDE, XIAO‐DAN ‐D CAI, MIKIO SHOJI, STEVEN G. YOUNKIN

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The ∼4 kD (39–43 amino acid) polypepride (amyloid β protein, Aβ) deposited as amyloid in Alzheimer's disease (AD) is derived from a set of 695–770 residue precursor proteins collectively referred to as the amyloid β‐protein precursor (βAPP). Using immunoblotting techniques, metabolic labeling, and sequencing we have analyzed βAPP derivatives in medium conditioned by (1) human mononuclear leukemic (K562) cells expressing a model βAP‐bearing carboxyl‐terminal βAPP derivative (2) human neuroblastoma (Ml7) cells transfected with constructs expressing full length βAPP and (3) M17 cells expressing only endogenous βAPP. In each case, we observed the release of a ∼4 kD βAPP derivative essentially identical to the Aβ found in AD amyloid. A similar, if not identical, βAPP fragment was readily detected in CSF from both Alzheimer's disease patients and controls. These observations indicate that the Aβ is produced and released by normal processing of the βAPP. To determine if the production of Aβ or Aβ‐tearing COOH‐terminal βAPP derivatives is altered in cells expressing the mutant βAPPs linked to familial AD, we have compared M17 cells expressing wild type βAPP with those expressing mutant βAPPs (βAPPΔI or βAPPΔNL). After continuous metabolic labeling for 8 hours, cells expressing the βAPPΔNL mutant showed a 5‐fold increase in the relative amount of an ∼ 11.4 kD Aβ‐bearing carboxyl‐terminal βAPP derivative, and they released 6‐fold more 4 kD Aβ into the medium. These observations provide strong evidence that (1) the pathway producing Aβ in cultured cells is highly relevant to AD and (2) the βAPPΔNL mutant causes AD because its processing is altered in a way that releases increased amounts of Aβ.

Original languageEnglish (US)
Pages (from-to)103-108
Number of pages6
JournalAnnals of the New York Academy of Sciences
Volume695
Issue number1
DOIs
StatePublished - Sep 1993

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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