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S4‐02‐04: Propagation of tau misfolding: A new mechanism for Alzheimer's disease?
Author(s) -
Diamond Marc I.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.461
Subject(s) - fibril , protein aggregation , biophysics , mechanism (biology) , cytosol , chemistry , neuroscience , tau protein , microbiology and biotechnology , protein folding , biology , alzheimer's disease , disease , biochemistry , physics , medicine , pathology , quantum mechanics , enzyme
and filament formation (e.g. neurofibrillary tangle (NFT)). Several genetic disorders may be associated with a primary or secondary tauopathy. A primary tauopathy occurs when there is a mutation in the coding or non-coding regions of the Tau gene: this leads to alterations of the tau protein sequence or of the ratio between threeand four-repeat tau, respectively. A secondary tauopathy occurs when there is a mutation in the Amyloid Precursor Protein (APP), Presenilin (PSEN1), Presenilin 2 (PSEN2), BRI2, or Niemann-Pick Disease Type C1 (NPC1) genes. Some Prion Protein (PRNP) gene mutations are associated with a secondary tauopathy. The mechanisms by which NFTs are produced are not well understood, particularly in secondary tauopathies. Methods: Neuropathologic studies were carried out using histologic, immunohistochemistical and electron microscopic methods. Genetic analysis was carried out on DNA extracted from brain tissue. Western blot analysis of tau was carried out on brain tissue from individuals with PRNP F198S. Results: We have studied brains of numerous patients affected with Gerstmann-SträusslerScheinker disease (GSS) or PrP cerebral amyloid angiopathy associated mutations PRNP F198S, D202N, Q217R, Q145X and Q160X. Y163X is also known to be associated with NFTs. We have found that PrP accumulation is mostly parenchymal in the missense mutations and both parenchymal and vascular in the nonsense mutations. NFTs are present in neurons in the cerebral cortex, subcortical nuclei and brain stem. The neurons of the cerebellar cortex appear to be consistently spared. Tau glial pathology is not seen. Electron microscopic analyses show that NFTs are composed of paired-helical filaments and are indistinguishable from those of AD. In Western blot, tau of GSS associated with the PRNP F198S and AD has indistinguishable electrophorectic mobility. Conclusions: Genetically-determined secondary tauopathies are characterized by the presence of NFTs that are ultrastructurally, immunohistochemically and biochemically indistinguishable from those seen in sporadic AD. These NFTs contain all six tau isoforms. We speculate that, in these conditions, common pathogenetic mechanisms may lead to tau dysfunction and neurodegeneration. Further analysis of secondary tauopathies is needed.