Neuronal expression of β-amyloid precursor protein Alzheimer mutations causes intracellular accumulation of a C-terminal fragment containing both the amyloid β and cytoplasmic domains

Donna L. McPhie, Robert K K Lee, Christopher B. Eckman, Daniel H. Olstein, Stephanie P. Durham, Debra Yager, Steven G Younkin, Richard J. Wurtman, Rachael L. Neve

Research output: Contribution to journalArticle

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Abstract

Five different Alzheimer mutations of the β-amyloid precursor protein (APP) were expressed in neurons via recombinant herpes simplex virus (HSV) vectors, and the levels of APP metabolites were quantified. The pre-dominant intracellular accumulation product was a C-terminal fragment of APP that co- migrated with the protein product of an HSV recombinant expressing the C- terminal 100 amino acids (C100) of APP, which is known to cause neurodegeneration. Fractionation studies revealed that the C-terminal fragment generated by expression of the Alzheimer mutations, like C100, partitioned into membrane fractions and was particularly enriched in synaptosomes. The processing abnormality caused by expression of the Alzheimer mutations occurs predominantly in neurons. Expression of these mutations or of C100 alone in neurons caused increased secretion of Aβ relative to that of neurons infected with wild type APP recombinant vectors. These data show that expression of APP mutations that cause familial Alzheimer's disease increases the intracellular accumulation of potentially amyloidogenic and neurotoxic C-terminal fragments of APP in neurons.

Original languageEnglish (US)
Pages (from-to)24743-24746
Number of pages4
JournalJournal of Biological Chemistry
Volume272
Issue number40
DOIs
StatePublished - Oct 3 1997

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Amyloid beta-Protein Precursor
Amyloid
Neurons
Mutation
Simplexvirus
Viruses
Synaptosomes
Fractionation
Metabolites
Alzheimer Disease
Membranes
Amino Acids
Processing
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Neuronal expression of β-amyloid precursor protein Alzheimer mutations causes intracellular accumulation of a C-terminal fragment containing both the amyloid β and cytoplasmic domains. / McPhie, Donna L.; Lee, Robert K K; Eckman, Christopher B.; Olstein, Daniel H.; Durham, Stephanie P.; Yager, Debra; Younkin, Steven G; Wurtman, Richard J.; Neve, Rachael L.

In: Journal of Biological Chemistry, Vol. 272, No. 40, 03.10.1997, p. 24743-24746.

Research output: Contribution to journalArticle

McPhie, Donna L. ; Lee, Robert K K ; Eckman, Christopher B. ; Olstein, Daniel H. ; Durham, Stephanie P. ; Yager, Debra ; Younkin, Steven G ; Wurtman, Richard J. ; Neve, Rachael L. / Neuronal expression of β-amyloid precursor protein Alzheimer mutations causes intracellular accumulation of a C-terminal fragment containing both the amyloid β and cytoplasmic domains. In: Journal of Biological Chemistry. 1997 ; Vol. 272, No. 40. pp. 24743-24746.
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