title: 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.
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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
authors.forename: M R
authors.initials: MR
authors.lastname: Kozlowski
authors.forename: A
authors.initials: A
authors.lastname: Spanoyannis
authors.forename: S P
authors.initials: SP
authors.lastname: Manly
authors.forename: S A
authors.initials: SA
authors.lastname: Fidel
authors.forename: R L
authors.initials: RL
authors.lastname: Neve
mesh_terms: 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
chemical_list: D016564:Amyloid beta-Protein Precursor; D003470:Culture Media; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D015320:Tachykinins