Location of Repository

Change in tau phosphorylation associated with neurodegeneration in the ME7 model of prion disease

By Ayodeji A. Asuni, V. Hugh Perry and Vincent O'Connor


Hyperphosphorylation of the microtubule-associated protein tau is a significant determinant in AD (Alzheimer's disease), where it is associated with disrupted axonal transport and probably causes synaptic dysfunction. Although less well studied, hyperphosphorylation has been observed in prion disease. We have investigated the expression of hyperphosphorylated tau in the hippocampus of mice infected with the ME7 prion agent. In ME7-infected animals, there is a selective loss of CA1 synapse, first discernable at 13 weeks of disease. There is a potential that dysfunctional axonal transport contributes to this synaptopathy. Thus investigating hyperphosphorylated tau that is dysfunctional in AD could illuminate whether and how they are significant in prion disease. We observed no differences in the levels of phosphorylated tau (using MC1, PHF-1 and CP13 antibodies) in detergent-soluble and detergent-insoluble fractions extracted from ME7- and NBH- (normal brain homogenate) treated animals across disease. In contrast, we observed an increase in phospho-tau staining for several epitopes using immunohistochemistry in ME7-infected hippocampal sections. Although the changes were not of the magnitude seen in AD tissue, clear differences for several phospho-tau species were seen in the CA1 and CA3 of ME7-treated animals (pSer(199-202)>pSer(214)>PHF-1 antibody). Temporally, these changes were restricted to animals at 20 weeks and none of the disease-related staining was associated with the axons or dendrites that hold CA1 synapses. These findings suggest that phosphorylation of tau at the epitopes examined does not underpin the early synaptic dysfunction. These data suggest that the changes in tau phosphorylation recorded here and observed by others relate to end-stage prion pathology when early dysfunctions have progressed to overt neuronal loss

Topics: R1
Year: 2010
OAI identifier: oai:eprints.soton.ac.uk:180209
Provided by: e-Prints Soton

Suggested articles



  1. (1993). Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding.
  2. (1987). Amyloid scrapie plaques in mice, and Alzheimer senile plaques, share common antigens with tau, a microtubule-associated protein.
  3. (2002). Analysis of the exon 1 polymorphism in the Tau gene in transmissible spongiform encephalopathies.
  4. (2003). Association of ATP synthase alpha-chain with neurofibrillary degeneration in Alzheimer’s disease.
  5. (2006). BSE infection in bovine PrP transgenic mice leads to hyperphosphorylation of tau-protein.
  6. (2000). Conformational change as one of the earliest alterations of tau in Alzheimer’s disease.
  7. (2008). Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein.
  8. H i r o k a w a
  9. H o r t o n ,A . C .a n dE h l e r s ,M .
  10. (2001). Highly increased CSF tau protein and decreased -amyloid (1–42) in sporadic CJD: a discrimination from Alzheimer’s disease?
  11. (2008). Human tau protein forms complex with PrP and some GSS- and fCJD-related PrP mutants possess stronger binding activities with tau in vitro.
  12. (1992). Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau.
  13. (2002). Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann–Str¨ aussler–Scheinker syndrome P102L mutation complicated with dementia.
  14. (2007). Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements.
  15. M a n d e l k o w ,E . M .a n dM a n d e l k o w
  16. (2008). Magnetic resonance spectroscopy and measurement of tau epitopes of autopsy proven sporadic Creutzfeldt–Jakob disease in a patient with non-specific initial EEG, MRI and negative 14-3-3 immunoblot.
  17. (1995). Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark): a novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262.
  18. (2000). Microtubule/MAP-affinity regulating kinase (MARK) is activated by phenylarsine oxide in situ and phosphorylates tau within its microtubule-binding domain.
  19. (2003). Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt–Jakob disease from other dementias.
  20. (2005). Prion disease incubation time is not affected in mice heterozygous for a dynein mutation.
  21. (1999). Purification of paired helical filament tau and normal tau from human brain tissue. Methods Enzymol.
  22. (1996). Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1.
  23. (1993). S c o t t ,C . W . ,S p r e e n ,R . C . ,H e r m a n ,J . L . ,C h o w ,F . P . ,D a v i s o n ,M . D . ,Y o u n g
  24. S h a h a n i ,N .a n dB r a n d t
  25. (2005). S t o k i n ,G . B . ,L i l l o ,C . ,F a l z o n e ,T . L . ,B r u s c h ,R . G . ,R o c k e n s t e i n ,E . ,M o u n t
  26. (2009). Selective presynaptic degeneration in the synaptopathy associated with ME7-induced hippocampal pathology.
  27. (2003). Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease.
  28. (2010). Synuclein deficiency in the C57BL/6JOlaHsd strain does not modify disease progression in the ME7-model of prion disease.
  29. (2008). Tauopathy in human and experimental variant Creutzfeldt–Jakob disease.
  30. (2000). Taxol impairs anterograde axonal transport of microinjected horseradish peroxidase in dorsal root ganglia neurons
  31. (2002). The complex relationship between soluble and insoluble tau in tauopathies revealed by efficient dephosphorylation and specific antibodies.
  32. (1999). The microtubule binding of Tau and high molecular weight Tau in apoptotic PC12 cells is impaired because of altered phosphorylation.
  33. (1999). The road less traveled: emerging principles of kinesin motor utilization.
  34. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular A and synaptic dysfunction.
  35. (2008). Unaltered SNARE complex formation in an in vivo model of prion disease.
  36. (2002). Unhampered prion neuroinvasion despite impaired fast axonal transport in transgenic mice overexpressing four-repeat tau.
  37. (2008). Why is the amyloid peptide of Alzheimer’s disease neurotoxic? Dalton Trans.,

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.