title: Proteasome degradation of brain cytosolic tau in Alzheimer's disease.
abstract: The proteasomal degradation of cytosolic, phosphorylation-independent tau in human brains is potentially linked to the pathogenesis of neurofibrillary pathology in Alzheimer's disease (AD). Previous studies showed that the active 20S proteasome core degrades recombinant tau effectively, which prompted this study to determine if there was evidence of proteasomal degradation of tau in human brain with a range of neurofibrillary pathology. Cytosolic proteins from temporal cortex were isolated from 30,000xgsupernatants by resolving in size-exclusion chromatogra-phy for assay of tau and proteasomal subunits by Western blots. Levels of tau and proteasome subunits varied from case to case, with a significant inverse correlation between the levels of tau and 20S β-subunits, and between 70-kDa tau and 11S β-subunits, suggesting that tau is a proteasomal substrate. The inability to detect tau in western blots on cases without neurofibrillary pathology is consistent with the hypothesis that the proteasome is capable of degrading normal tau with an intact projection domain at the amino-terminal end; however, as proteasomal function becomes impaired during aging, tau clearance is impeded. Tau accumulates in progressively larger and more heterogeneous forms in brains with neurofibrillary pathology. Under normal conditions, non-proteasomal proteases are capable of digesting recombinant-tau from both the amino- and carboxyl-terminal ends toward the mid-section, but are lack of chaperon-like activity to unfold carboxyl-terminal truncated tau accumulated in AD. Our results support the hypothesis that failure of proteasomal and non-proteasomal proteolytic clearance mechanisms leads to tau accumulation and progressive neurofibrillary degeneration in AD.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine 4500 San Pablo Road, Jacksonville, FL, USA. yen.samuel@mayo.edu
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Yen
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D000704:Analysis of Variance; D015153:Blotting, Western; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology; D002850:Chromatography, Gel; D003600:Cytosol / Q000201:enzymology; D005260:Female; D005431:Florida; D006801:Humans; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D008970:Molecular Weight; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits; D012044:Regression Analysis; D013702:Temporal Lobe / Q000201:enzymology* / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex