Journal of Neuroscience, Vol 10, 3295-3304, Copyright © 1990 by Society for Neuroscience
Alz-50 recognizes a phosphorylated epitope of tau protein
K Ueda, E Masliah, T Saitoh, SL Bakalis, H Scoble and KS Kosik
Department of Neurosciences School of Medicine, University of California, San Diego, La Jolla 92093.
Alz-50 is a monoclonal antibody that detects antigens enriched in the brain
tissue of Alzheimer's disease (AD) patients. Although Alz-50 recognizes
tau, an identified integral constituent of the AD paired helical filament
(PHF), the exact nature of the antigenic site is unknown. An immunoblot
analysis demonstrated that the antigenic sites to Alz-50 are diminished by
acid phosphatase treatment. Consistent with this finding, Alz-50 antigens
were more concentrated in brain homogenates prepared with phosphatase
inhibitors. The epitope in tau with which Alz-50 reacts is located in the
carboxy terminus within a 14- amino acid region from just beyond the
microtubule-binding repeats to the carboxy terminus. An isolated
carboxy-terminal chymotryptic peptide from bovine brain tau reactive with
Alz-50 was analyzed by fast-atom- bombardment mass spectroscopy (FAB-MS)
and was found to be present as both a monophosphopeptide and a
nonphosphorylated peptide. The immunohistological analysis has demonstrated
that Alz-50 staining of neurofibrillary tangles (NFTs) is sensitive to acid
phosphatase but not to alkaline phosphatase. Furthermore, Alz-50 staining
of NFTs was effectively adsorbed by a high concentration of phosphoserine
but not by serine or phosphothreonine. These results strongly suggest that
Alz- 50 recognizes a phosphorylated epitope in the carboxy terminus of tau
which has not been previously detected by using alkaline phosphatase. The
strong Alz-50 staining in AD samples may represent another association
between a phosphorylation state and neurofibrillary lesions. As a marker of
the inchoate tangle-bearing neuron, the characterization of the Alz-50
epitope in tau offers a partial molecular basis for the modifications that
contribute to the assembly of PHFs.
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