The Alzheimer amyloid precursor is associated with the detergent-insoluble cytoskeleton.
The amyloid beta-protein (A beta P), the main component of neuritic plaques in Alzheimer's disease (AD), is derived by unknown mechanisms from a family of amyloid precursor proteins (APPs). Using a detergent extraction procedure, we have found that in brain and in neural cell lines, 50-90% of APP is bound to detergent-insoluble cytoskeleton. Labeling experiments performed in a C6 glioma cell line indicated that both cell surface and intracellular APPs are associated with the cytoskeleton. This association requires intact microtubules and is modulated by protein phosphorylation and by cell density. These findings suggest that the function of cellular APP, presently unknown, involves the cytoskeleton and particularly microtubules. The dynamic nature of the binding and its dependence on microtubules and protein phosphorylation suggest it as a possible target in AD, where abnormal cytoskeletal structures and protein phosphorylation have been reported. Altered cytoskeletal binding of APP might lead to its aberrant proteolysis and generation of the A beta P.
Refolo
L M
LM
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
Wittenberg
I S
IS
Friedrich
V L
VL
Robakis
N K
NK
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000648:ultrastructure*; D003902:Detergents; D007425:Intracellular Membranes / Q000378:metabolism; D008870:Microtubules / Q000502:physiology; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism*; D012995:Solubility; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003598:Cytoskeletal Proteins; D003902:Detergents; D011498:Protein Precursors