Journal of Neuroscience, Vol 12, 1679-1687, Copyright © 1992 by Society for Neuroscience
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
MR Kozlowski, A Spanoyannis, SP Manly, SA Fidel and RL Neve
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
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.
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