Early accumulation of p62 in neurofibrillary tangles in Alzheimer's disease: possible role in tangle formation

Neurofibrillary tangles (NFTs) and neuritic plaques (NPs) are two major histopathological lesions in Alzheimer's disease (AD). Although their aetiological relationship is unclear, both NFTs and dystrophic neurites of NPs display immunoreactivity for ubiquitin. This suggests that dysfunction in ubiquitin-mediated proteolysis and the resulting accumulation of ubiquitin-conjugated proteins may contribute to the origination of dystrophic neurites and NFTs. We recently discovered a novel constituent of neuropathological protein aggregates, ubiquitin-binding protein p62, with evidence that the accumulation of ubiquitin-conjugated proteins and p62 into cytoplasmic inclusions might be interconnected. In the present work we examined in detail the role of p62 in AD-type pathology, i.e. NFTs, NPs and neuropil threads. Using immunohistochemistry for p62, ubiquitin and hyperphosphorylated tau, we analysed parietal cortical samples of 15 clinicopathologically verified AD cases and nine nondemented aged subjects with abundant NPs. We found that p62 immunoreactivity appears early during neurofibrillary pathogenesis and is invariably and stably present in NFTs. In contrast, p62 was absent or barely detectable in neuropil threads. Furthermore, NP-associated dystrophic neurites were generally devoid of p62, regardless of their content of hyperphosphorylated tau and/or ubiquitin. The results suggest that early involvement of p62 might be critical in the aggregation of hyperphosphorylated tau into perikaryal aggregates, i.e. NFTs.