PMID- 22817713
OWN - NLM
STAT- MEDLINE
DCOM- 20121207
LR  - 20220330
IS  - 1470-8752 (Electronic)
IS  - 0300-5127 (Print)
IS  - 0300-5127 (Linking)
VI  - 40
IP  - 4
DP  - 2012 Aug
TI  - Tau oligomers and tau toxicity in neurodegenerative disease.
PG  - 667-71
LID - 10.1042/BST20120134 [doi]
AB  - AD (Alzheimer's disease) is a progressive neurodegenerative disorder 
      characterized by the extracellular accumulation of amyloid beta-peptide and the 
      intracellular accumulation of tau. Although there is much evidence linking tau to 
      neurodegeneration, the precise mechanism of tau-mediated neurotoxicity remains 
      elusive. The presence of tau-positive pre-tangle neurons lacking neurofibrillary 
      tangles has been reported in AD brain tissue. In order to study this 
      non-fibrillar tau, we generated a novel monoclonal antibody, named TOC1 (tau 
      oligomeric complex 1), which selectively labels tau dimers and oligomers, but 
      does not label filaments. Time-course analysis and antibody labelling indicates 
      that oligomers appear as an early event in AD pathogenesis. Using a squid 
      axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT 
      (fast axonal transport), whereas monomeric tau has no effect. This inhibition 
      requires a small stretch of N-terminal amino acids termed the PAD 
      (phosphatase-activation domain). Using a PAD-specific antibody, TNT1 (tau 
      N-terminal 1), we demonstrate that PAD exposure is increased in diseased neurons 
      and this leads to an increase in FAT inhibition. Antibody co-labelling with the 
      early-AD marker AT8 indicates that, similar to TOC1, TNT1 expression represents 
      an early event in AD pathogenesis. Finally, the effects of the molecular 
      chaperone Hsp70 (heat-shock protein 70) were also investigated within the squid 
      axoplasm assay. We illustrate that Hsp70 preferentially binds to tau oligomers 
      over filaments and prevents anterograde FAT inhibition observed with a mixture of 
      both forms of aggregated tau. Together, these findings support the hypothesis 
      that tau oligomers are the toxic form of tau in neurodegenerative disease.
FAU - Ward, Sarah M
AU  - Ward SM
AD  - Department of Cell and Molecular Biology, Feinberg School of Medicine, 
      Northwestern University, Chicago, IL 60611, USA. sallward77@gmail.com
FAU - Himmelstein, Diana S
AU  - Himmelstein DS
FAU - Lancia, Jody K
AU  - Lancia JK
FAU - Binder, Lester I
AU  - Binder LI
LA  - eng
GR  - AG014449/AG/NIA NIH HHS/United States
GR  - T32 AG20506/AG/NIA NIH HHS/United States
GR  - P01 AG009466/AG/NIA NIH HHS/United States
GR  - T32 AG020506/AG/NIA NIH HHS/United States
GR  - P01 AG014449/AG/NIA NIH HHS/United States
GR  - AG09466/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
PL  - England
TA  - Biochem Soc Trans
JT  - Biochemical Society transactions
JID - 7506897
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (tau Proteins)
SB  - IM
MH  - Alzheimer Disease/metabolism
MH  - Animals
MH  - HSP70 Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Neurodegenerative Diseases/*metabolism
MH  - Protein Multimerization
MH  - tau Proteins/chemistry/*metabolism
PMC - PMC3704193
MID - NIHMS475730
EDAT- 2012/07/24 06:00
MHDA- 2012/12/12 06:00
PMCR- 2013/07/08
CRDT- 2012/07/24 06:00
PHST- 2012/07/24 06:00 [entrez]
PHST- 2012/07/24 06:00 [pubmed]
PHST- 2012/12/12 06:00 [medline]
PHST- 2013/07/08 00:00 [pmc-release]
AID - BST20120134 [pii]
AID - 10.1042/BST20120134 [doi]
PST - ppublish
SO  - Biochem Soc Trans. 2012 Aug;40(4):667-71. doi: 10.1042/BST20120134.