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Int J Clin Exp Pathol 2011;4(4):385-402

Original Ariticle
Proteasome degradation of brain cytosolic tau in Alzheimer’s disease

Samuel S. Yen

Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, USA.

Received April 10, 2011; accepted April 19, 2011; Epub April, 2011, published April, 2011

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 30,000xg supernatants by
resolving in size-exclusion chromatography 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. (IJCEP1104007)

Keywords: Alzheimer’s disease, immunoblotting, neurofibrillary, PHF-tau, proteasome, size- exclusion chromatography, tau

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Address all correspondence to:
Samuel S. Yen, PhD
Department of Neuroscience
Mayo Clinic College of Medicine
4500 San Pablo Road
Jacksonville, FL 32224
Phone: 904-953-2585 or 1066
Fax: 904-953-7117
E-Mail:
yen.samuel@mayo.edu