R. De Silva1,2, Tammaryn Lashley3, G M Gibb4, Diane P. Hanger4, A. Hope2, A R Reid2, Rina Bandopadhyay2, Michelle A. Utton3, Catherine Strand3, T.P. Jowett5, Naheed L. Khan6, Brian H. Anderton4, Nicholas Wood1, Janice L. Holton3, Tamás Révész3, Andrew J. Lees1,2
1Department of Molecular Neuroscience and
2Reta Lila Weston Institute of Neurological Studies and
3Neuropathology, Institute of Neurology, London, UK, and
4Departments of Neuroscience, and
5UCL Monoclonal Antibody Unit Department of Immunology & Molecular Pathology, University College London, London, UK,
6Neuropathology, Institute of Psychiatry, King's College, London, UK
Tóm tắt
Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in the tauopathies, which include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17), progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Tau isoform composition and cellular and regional distribution as well as morphology of these inclusions vary in each disorder. Recently, several pathological missense and exon 10 splice‐donor site mutations of the tau gene were iden‐tified in FTDP‐17. Exon 10 codes for the second of four microtubule‐binding repeat domains. The splice‐site mutations result in increased inclusion of exon 10 which causes a relative increase in tau isoforms containing four microtubule‐binding repeat domains over those containing three repeat domains. This could be a central aetiological mechanism in FTDP‐17 and, perhaps, other related tauopathies. We have investigated changes in the ratio and distribution of three‐repeat and four‐repeat tau in the different tauopathies as a basis of the phenotypic range of these disorders and the selective vulnerability of different subsets of neurones. In this study, we have developed two monoclonal antibodies, RD3 and RD4 that effectively distinguish these closely related tau isoforms. These new isoform‐specific antibodies are useful tools for analysing tau isoform expression and distribution as well as pathological changes in the human brain.
