Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function.
The accumulation of amyloid-beta (Abeta) into plaques is a hallmark feature of Alzheimer's disease (AD). While amyloid precursor protein (APP)-related proteins are found in most organisms, only Abeta fragments from human APP have been shown to induce amyloid deposits and progressive neurodegeneration. Therefore, it was suggested that neurotoxic effects are a specific property of human Abeta. Here we show that Abeta fragments derived from the Drosophila orthologue APPL aggregate into intracellular fibrils, amyloid deposits, and cause age-dependent behavioral deficits and neurodegeneration. We also show that APPL can be cleaved by a novel fly beta-secretase-like enzyme. This suggests that Abeta-induced neurotoxicity is a conserved function of APP proteins whereby the lack of conservation in the primary sequence indicates that secondary structural aspects determine their pathogenesis. In addition, we found that the behavioral phenotypes precede extracellular amyloid deposit formation, supporting results that intracellular Abeta plays a key role in AD.
Carmine-Simmen
Katia
K
Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Proctor
Thomas
T
Tschäpe
Jakob
J
Poeck
Burkhard
B
Triphan
Tilman
T
Strauss
Roland
R
Kretzschmar
Doris
D
D000375:Aging; D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D007150:Immunohistochemistry; D008027:Light; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics
C545487:APP protein, human; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; C066839:Appl protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D053829:Amyloid Precursor Protein Secretases