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American Journal of Pathology, Vol 142, 387-394, Copyright © 1993 by American Society for Investigative Pathology

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Heterogeneity of tau proteins in Alzheimer's disease. Evidence for increased expression of an isoform and preferential distribution of a phosphorylated isoform in neurites

WK Liu, DW Dickson and SH Yen
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.

PHF-tau, a modified form of tau in Alzheimer diseased brains, is composed of proteins of molecular weight 68, 64, and 60 kd. The 68-kd PHF-tau has been reported to be encoded by a tau transcript containing both exons 2 and 3. The 64-kd protein contains exon 2, but not exon 3, and the 60-kd protein contains neither exons 2 nor 3. To study the proportion of different tau isoforms in PHF-tau and normal tau, we raised antibodies to exon 2 (E-2) and exon 3 (E-3). By immunoblots, about 74% of the PHF-tau contained exon 2, and 25% contained exon 3; whereas in normal tau, 82 to 90% contained exon 2, and no more than 5% contained exon 3. Enzyme-linked immunosorbent assays demonstrated that PHF-tau was 38% less reactive with E-2 and 79% more reactive with E-3 than normal tau. Alkaline phosphatase treatment increased the E-2 immunoreactivity of PHF-tau by 120% and normal tau by 38%, but it had no effect on E-3 immunoreactivity. The dephosphorylated PHF-tau and normal tau were similar in E-2 immunoreactivities. Phosphatase treatment of Alzheimer's diseased brain sections increased the number of E-2 immunoreactive neuropil threads and senile plaque neurites but had very little effect on the number of immunoreactive neurofibrillary tangles. The results suggest that PHF-tau contains proportionally more isoforms with E-3 than normal tau; that the E-2 epitope is more phosphorylated in PHF-tau than in normal tau; and that the phosphorylated E-2 epitope of PHF-tau is preferentially located in neurites.

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