The neurotoxic carboxy-terminal fragment of the Alzheimer amyloid precursor binds specifically to a neuronal cell surface molecule: pH dependence of the neurotoxicity and the binding.
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.
Kozlowski
M R
MR
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
Spanoyannis
A
A
Manly
S P
SP
Fidel
S A
SA
Neve
R L
RL
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D003470:Culture Media; D006863:Hydrogen-Ion Concentration; D009154:Mutation; D009414:Nerve Growth Factors / Q000494:pharmacology; D009420:Nervous System / Q000187:drug effects; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D015320:Tachykinins / Q000494:pharmacology; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D003470:Culture Media; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D015320:Tachykinins