Phosphorylation of paired helical filament tau in Alzheimer's disease neurofibrillary lesions: focusing on phosphatases.
The major brain abnormalities in patients with Alzheimer's disease (AD) include extracellular deposits of beta-amyloid, intraneuronal neurofibrillary lesions, and the massive loss of specific subsets of telencephalic neurons. Neurofibrillary lesions contain paired helical filaments (PHFs) that accumulate in the perikarya (e.g., neurofibrillary tangles) and processes (e.g., dystrophic neurites, neuropil threads) of selectively vulnerable telencephalic neurons. The subunits of PHFs are derivatized forms of central nervous system (CNS) tau proteins (CNS tau) known collectively as PHFtau. Until very recently it was thought that the aberrant phosphorylation of PHFtau was the most salient difference between normal human CNS tau and PHFtau. However, this view required modification when it was shown that fetal and biopsy-derived human CNS tau proteins were phosphorylated at nearly all of the same sites found in PHFtau, albeit to a lesser extent. More significantly, these and other studies may be interpreted to suggest that the abnormal phosphorylation of PHFtau may result from the failure of protein phosphatases (i.e., PP2A and 2B) to dephosphorylate PHFtau. In this review, we summarize current understanding of the role of kinases and phosphatases in pathogenesis of PHFtau. We then consider how the formation PHFtau in neurons could disrupt the microtubule network, impair axonal transport, and compromise the viability of neurons, thereby contributing to the onset and progression of AD.
Trojanowski
J Q
JQ
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA.
Lee
V M
VM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001370:Axonal Transport; D018450:Disease Progression; D005326:Fetal Proteins / Q000378:metabolism; D006801:Humans; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D005326:Fetal Proteins; D009419:Nerve Tissue Proteins; D016875:tau Proteins; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases