In the neurofibrillary pathology of
Alzheimer's disease (AD), neurofibrillary tangles (NFTs) contain paired helical filaments (PHFs) as their major fibrous component. Abnormally hyperphosphorylated,
microtubule-associated protein tau is the major
protein subunit of PHFs. A recent in vitro study showed that PHF tangles from AD brains are highly glycosylated, whereas no
glycan is detected in normal tau. Deglycosylation of PHF tangles converts them into bundles of straight filaments and restores their accessibility to microtubules. We showed that PHF tangles from AD brain tissue were associated with specific
glycan molecules by double immunostaining with
peroxidase and
alkaline phosphatase labeling. Intracellular tangles and dystrophic neurites in a
neuritic plaque with abnormally hyperphosphorylated tau, detected with the
monoclonal antibodies AT-8 and anti-tau-2, were also positive with
lectin Galanthus nivalis agglutinin (GNA) which recognizes both the N- and O-glycosidically linked saccharides. Colocalization was not seen in the extracellular tangles and
amyloid deposition, suggesting that the glycosylation of tau might be associated with the early phase of insoluble NFT formation. Thus, although abnormal phosphorylation might promote aggregation of tau and inhibition of the assembly of microtubules, glycosylation mediated by a GNA-positive
glycan appears to be responsible for the formation of the PHF structures in vivo.