G Protein-Mediated Neuronal DNA Fragmentation Induced by Familial Alzheimer's Disease-Associated Mutants of APP

Missense mutations in the 695-amino acid form of the amyloid precursor protein (APP$_{695}$) cosegregate with disease phenotype in families with dominantly inherited Alzheimer's disease. These mutations convert valine at position 642 to isoleucine, phenylalanine, or glycine. Expression of these...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 1996-05, Vol.272 (5266), p.1349-1352
Main Authors: Yamatsuji, Tomoki, Matsui, Takashi, Okamoto, Takashi, Komatsuzaki, Katsumi, Takeda, Shizu, Fukumoto, Hiroaki, Iwatsubo, Takeshi, Suzuki, Nobuhiro, Asami-Odaka, Asano, Ireland, Scott, Kinane, T. Bernard, Giambarella, Ugo, Nishimoto, Ikuo
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer's disease
Amino acids
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - chemistry
Amyloid beta-Protein Precursor - genetics
Amyloid beta-Protein Precursor - physiology
Amyloidosis
Animals
Antibodies
Apoptosis
Base Sequence
Biological and medical sciences
Cell lines
Cellular immunity
Complementary DNA
Culture Media, Conditioned
Cultured cells
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Dementia
Deoxyribonucleic acid
DNA
DNA - metabolism
DNA fragmentation
Genetic aspects
Genetic mutation
GTP-Binding Proteins - physiology
Humans
Hybrid Cells
Medical sciences
Mice
Molecular Sequence Data
Mutagenesis, Site-Directed
Mutation
Neurology
Neurons
Neurons - cytology
Neurons - metabolism
Nucleosomes - metabolism
Observation
Peptide Fragments - metabolism
Proteins
Rats
Transfection
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Description
Summary:Missense mutations in the 695-amino acid form of the amyloid precursor protein (APP$_{695}$) cosegregate with disease phenotype in families with dominantly inherited Alzheimer's disease. These mutations convert valine at position 642 to isoleucine, phenylalanine, or glycine. Expression of these mutant proteins, but not of normal APP$_{695}$, was shown to induce nucleosomal DNA fragmentation in neuronal cells. Induction of DNA fragmentation required the cytoplasmic domain of the mutants and appeared to be mediated by heterotrimeric guanosine triphosphate-binding proteins (G proteins).
ISSN:0036-8075
1095-9203
DOI:10.1126/science.272.5266.1349