Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40
Copyright policy )Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40
AbstractFrame‐shifted amyloid precursor protein (APP+1), which has a truncated out‐of‐frame C‐terminus, accumulates in the neuropathological hallmarks of patients with Alzheimer's disease pathology. To study a possible involvement of APP+1 in the pathogenesis of Alzheimer's disease, we expressed APP695 and APP+1 in the HEK293 cell‐line and studied whether the processing of APP695 was affected. APP+1 is a secretory protein, but high expression of APP695 and APP+1 results in the formation of intracellular aggregate‐like structures containing both proteins and Fe65, an adaptor protein that interacts with APP695. APP+1 is shown to interact with APP695, suggesting that these structures consist of functional protein complexes. Such an interaction can also be anticipated in post‐mortem brains of young Down's syndrome patients without any sign of neuropathology. Here we observed APP+1 immunoreactivity in beaded fibres. Additional support for functional consequences on the processing of APP695 comes from a 1.4‐fold increase in levels of secreted amyloid β40 in cells co‐expressing APP695 and APP+1, although APP+1 itself does not contain the amyloid β sequence. Taken together, these data show that co‐expression of APP695 and APP+1 affects the processing of APP695 in a pro‐amyloidogenic way and this could gradually contribute to Alzheimer's disease pathology, as has been implicated in Down's syndrome patients.
- University of Salford United Kingdom
- Salford Royal NHS Foundation Trust United Kingdom
- Graduate School Neurosciences Amsterdam Rotterdam Netherlands
- Aventis Pharma India
- Salford Royal Hospital United Kingdom
Adult, Male, Amyloid beta-Peptides, Macromolecular Substances, Infant, Newborn, Gene Expression, Nuclear Proteins, Nerve Tissue Proteins, Kidney, Peptide Fragments, Cell Line, Amyloid beta-Protein Precursor, Alzheimer Disease, Humans, Female, Down Syndrome, Child, Frameshift Mutation, Protein Processing, Post-Translational, Protein Binding
Adult, Male, Amyloid beta-Peptides, Macromolecular Substances, Infant, Newborn, Gene Expression, Nuclear Proteins, Nerve Tissue Proteins, Kidney, Peptide Fragments, Cell Line, Amyloid beta-Protein Precursor, Alzheimer Disease, Humans, Female, Down Syndrome, Child, Frameshift Mutation, Protein Processing, Post-Translational, Protein Binding
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