Abstract
Accumulation of abnormally modified tau protein (PHF-tau) is the principal intracellular lesion in a variety of neurodegenerative diseases, including Alzheimer's Disease (AD), but the cellular mechanisms underlying this accumulation are unknown. In this study, the cellular metabolism of PHF-tau purified from AD brain was investigated by microinjecting it into identified central neurons of the lamprey, a lower vertebrate. Dephosphorylation of 2 critical epitopes (the PHF-1 and TAU-1 sites), occurred within a few hours of PHF-tau microinjection, while proteolysis was complete by 2 days. These results constitute the first demonstration of the intracellular degradation of PHF-tau in an experimental in vivo system and suggest that the degradation of PHF-tau in situ is preceded by dephosphorylation. They also suggest that intracellular PHF-tau accumulation is primarily due to the failure of normal dephosphorylation and/or proteolytic mechanisms during neurofibrillary degenerative disease.