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Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40
Author(s) -
Van Dijk R.,
Fischer D. F.,
Sluijs J. A.,
Sonnemans M. A. F.,
Hobo B.,
Mercken L.,
Mann D. M. A.,
Hol E. M.,
Van Leeuwen F. W.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02528.x
Subject(s) - amyloid precursor protein , pathogenesis , p3 peptide , bace1 as , amyloid (mycology) , neuropathology , alzheimer's disease , intracellular , biochemistry of alzheimer's disease , disease , chemistry , endocrinology , microbiology and biotechnology , medicine , biology , pathology
Frame‐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 APP 695 and APP +1 in the HEK293 cell‐line and studied whether the processing of APP 695 was affected. APP +1 is a secretory protein, but high expression of APP 695 and APP +1 results in the formation of intracellular aggregate‐like structures containing both proteins and Fe65, an adaptor protein that interacts with APP 695 . APP +1 is shown to interact with APP 695 , 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 APP 695 comes from a 1.4‐fold increase in levels of secreted amyloid β 40 in cells co‐expressing APP 695 and APP +1 , although APP +1 itself does not contain the amyloid β sequence. Taken together, these data show that co‐expression of APP 695 and APP +1 affects the processing of APP 695 in a pro‐amyloidogenic way and this could gradually contribute to Alzheimer's disease pathology, as has been implicated in Down's syndrome patients.