Contents

Search

paired helical filament (PHF)

Structure: - pairs of approximately 10 nm filaments wound into helices with a periodicity of 160 nm visible on electron microscopy - width varies between 10-22 nm - the major component of PHF is a hyperphosphorylated form of microtubule-associated protein tau.* - PHF are composed of disulfide-linked antiparallel hyperphosphorylated tau proteins - oxidized tau-phosphate dimer with insert 3 * a constitutively activated form of CDK5/p23-35 may hyperphosphorylate tau * glycogen synthase kinase 3-beta (GSK3-beta) has also been implicated in hyperphosphorylation of tau Pathology: - PHF are the major component of neuropil threads & neurofibrillary tangles of Alzheimer's disease (AD). - PHF may also be seen in some but not all dystrophic neurites associated with neuritic plaques (amyloid plaques). - PHF tau may be truncated of its C-terminal 20 amino acid residues. - proteolysis by one of several caspases at Asp-421 is implicated.[7] - dendrites & perikarya may contain PHF. [1] - the mechanisms underlying PHF formation are uncertain but hyperphosphorylation of tau may disengage it from microtubules [5], increasing the soluble pool of tau - certain types of phosphorylation of tau (by MAPK & GSK3, by MARK & PKA - at KXGS motifs within repeat region, especially Ser-262 & Ser-214) tend to inhibit PHF formation [6]

Related

Alzheimer's disease (AD) CDK5/p23-35 activator complex glycogen synthase kinase 3-beta (GSK3B) neurofibrillary tangle (NFT)

General

abnormal morphologic structure (malformation)

Properties

PATHOLOGY: Alzheimer's disease

References

  1. Gray et al Neuropathol Appl Neurobiol 13:91 1987 (in dendrites)
  2. Mori et al Science 235:1641 1987
  3. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  4. Maccioni et al The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Archives of Medical Research 32:367, 2001 PMID: 11578751
  5. Lee VM et al, Neurodegenerative tauopathies Annu Rev Neurosci 24:1121-59, 2001 PMID: 11520939
  6. Friedhoff P, von Bergen M, Mandelkow EM, Mandelkow E. Structure of tau protein and assembly into paired helical filaments. Biochim Biophys Acta. 2000 Jul 26;1502(1):122-32. Review. PMID: 10899437
  7. Gamblin TC et al, Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A. Aug 19;100(17):10032-7. 2003 PMID: 12888622
  8. Ksiezak-Reding H, Wall JS. Characterization of paired helical filaments by scanning transmission electron microscopy. Microsc Res Tech. 2005 Jul;67(3-4):126-40. Review. PMID: 16104001