Abstract
One of the hallmarks of Alzheimer's disease neurodegeneration is the accumulation of deposits of amyloid in neuritic plaques and in the cerebral vasculature. Recent studies have implicated carboxy-terminal fragments of the Alzheimer amyloid precursor protein (beta APP) in the processes of amyloidogenesis and neurodegeneration. In particular, the carboxy-terminal 104 amino acids of beta APP (beta APP-C104) have been shown to cause amyloid-like fibrils when expressed in non-neuronal cells and to cause the degeneration of neuronal cells. These data suggest that it may play a role in the development of the progressive neuropathology of Alzheimer's disease. We hypothesized that beta APP-C104 may cause the degeneration of neurons by interacting with a cell surface receptor. In the present report, we show that beta APP-C104 synthesized in vitro binds specifically and with high affinity to the surface of NGF-treated PC12 cells. Both the cell surface binding and the neurotoxicity of beta APP-C104 are pH dependent and are not inhibited by tachykinins. Mutational analysis suggests that both the binding and the neurotoxicity are dependent at least in part on the presence of a tyrosine residue that is a potential site of phosphorylation at the carboxy terminus of the fragment.