Comparative distribution of tau phosphorylated at Ser262 in pre-tangles and tangles

The Phospho-Ser(262) epitope of phosphorylated tau, which accumulates in tangles in Alzheimer's disease (AD) brains, has been shown to have a strong disruptive effect on microtubules. Using antibodies which specifically recognize the Phospho-Ser(262) of tau, we compared the presence of this epitope in normal appearing neurons (pre-tangles) and tangles, with the presence of Phospho-Ser(199/202) (AT-8) and Phospho-Ser(396/404) (PHF-1) epitopes. All antibodies visualized lightly or darkly stained pre-tangles, neurons with immunoreactive clumps, intracellular and extracellular tangles. Pre-tangles were more abundant in control cases which showed some pathology, when compared with AD brains. Immunoreactivity for Phospho-Ser(262) was preferentially present in intracellular and extracellular tangles and was found in a significantly smaller number of pre-tangles when compared with the other epitopes. These results indicate the presence of various epitopes of Phospho-Tau in a substantial number of pre-tangles which may represent an early marker of tangle formation. The differential distribution of various epitopes suggests that the presence of the Phospho-Ser(262) epitope of tau either accelerates the transition form pre-tangle to tangle, or appears later than the other epitopes in the process of tangle formation.