Currently, there is no biochemical marker clinically available to test for the presence of Alzheimer's disease (AD). Recent studies suggest that the core component of AD-associated neurofibrillary tangles (NFTs), the microtubule-associated protein tau, might be present in CSF. This study focuses on establishing both the presence of tau in CSF and its potential utility in the diagnosis of AD. We obtained CSF from 181 individuals; 71 of these were diagnosed as having probable AD by NINCDS-ADRDA criteria. The remaining 110 individuals were divided into three groups: (1) age-matched demented non-AD patients (n = 25), (2) neurologic controls (n = 59), and (3) other controls (n = 26). We developed a sensitive enzyme-linked immunosorbent tau assay using monoclonal antibodies prepared against recombinant human tau. We confirmed specificity of the antibodies by a combination of immunoprecipitation and immunoblot results. By this assay we measured that the AD population has a mean level of tau 50% greater than the non-AD dementia patients. Comparing AD patients with all other groups, the difference in tau levels as analyzed by one-way ANOVA is highly statistically significant (p < 0.001). Postmortem analysis of two AD patients with high levels of CSF tau revealed a high density of NFTs in the hippocampus. There was no significant correlation between tau and age in the non-AD groups. This study suggests that CSF tau is elevated in AD and might be a useful aid in antemortem diagnosis.

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Our previous studies on 7-hydroxymethyl-12-methylbenz[a]anthracene and 6-hydroxymethylbenzo[a]pyrene showed that cytosolic sulfotransferase activity plays a major role in the formation of hepatic benzylic DNA and RNA adducts by these carcinogens in rats. In the present study, we found similar sulfotransferase activity in rat liver cytosol which activates 9-hydroxymethyl-10-methylanthracene (HMA) and 1-hydroxymethylpyrene (HMP) to electrophilic sulfuric acid ester metabolites. Thus, incubation of these nonbay region hydrocarbons with calf thymus DNA in the presence of liver cytosol fortified with the sulfo-group donor, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) produced benzylic DNA adducts that were chromatographically identical to those obtained by the reactions of the corresponding sulfuric acid esters with deoxyguanosine and deoxyadenosine. These adducts were also produced in the livers of infant rats injected i.p. with 0.25 mumol/g body wt of HMA or HMP. Administration of comparable doses of 9-sulfooxymethyl-10-methylanthracene (SMA) and 1-sulfooxymethylpyrene (SMP) resulted in much higher levels of hepatic benzylic DNA adducts than did the parent hydroxymethyl hydrocarbons. Both HMA and HMP induced His+ revertants in Salmonella typhimurium TA98 when preincubated with these bacteria in the presence of rat liver cytosol and PAPS. This sulfotransferase-mediated mutagenicity of HMA and HMP was reduced by dehydroepiandrosterone, an inhibitor of hepatic sulfotransferase activity for these hydrocarbons. SMA and SMP were directly mutagenic and their intrinsic bacterial mutagenicity was inhibited by glutathione (GSH) and GSH-S-transferase activity. Chloride ion at physiological concentrations enhanced the bacterial mutagenicity of SMA through the formation of 9-chloromethyl-10-methylanthracene as previously observed for SMP by Henschler et al. In contrast to the higher mutagenicity of 1-chloromethylpyrene (CMP) than SMP in bacteria, CMP formed smaller amounts of hepatic benzylic DNA adducts in rats than the sulfuric acid ester. SMA and SMP were weak skin tumor initiators in the mouse, but they were more active than HMA and HMP in this regard.