Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule‐binding repeat domains as demonstrated by new specific monoclonal antibodies

Abstract

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 identified 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.

Aging Analysis Reveals Slowed Tau Turnover and Enhanced Stress Response in a Mouse Model of Tauopathy

“…In normal adult mice, however, murine tau exclusively becomes 4R. 21 Antibodies have been previously generated to specifically recognize 3R tau species 22,23 and we used these antibodies to determine whether 3R tau was present at different time points in the rTg4510 in response to high levels of 4R human tau.…”

Clinical and pathological features of an Alzheimer's disease patient with the MAPT ΔK280 mutation

“…One set of sections was immunostained for insoluble, pathological tau proteins by a standard immunoperoxidase method using the phosphodependent tau antibody AT8 (1:750; Innogenetics, Belgium; against phosphorylated Ser 202 / Thr 205 tau epitopes). Other sets of sections were stained with the 3R-and 4R-tau specific monoclonal antibodies, RD3 (1:3000; Upstate/Chemicon, Dundee, UK) and RD4 (1:100; Upstate/Chemicon, Dundee, UK), respectively, as described (de Silva et al, 2003). A second set was immunostained with anti-Aβ antibody (1:100; Dako, Ely, UK) for Alzheimer's disease β-amyloid pathology.…”

Single cell gene expression profiling in Alzheimer’s disease

“…For example, protein expression level studies link alterations in 3Rtau expression to NFT formation in AD, whereas alterations in 4Rtau expression levels are linked to tauopathies such as progressive supranuclear palsy and corticobasal degeneration. 81,[201][202][203][204][205] These data suggest a subtle, yet pervasive change in gene dosage of 3Rtau and 4Rtau within vulnerable neurons in MCI and AD, which does not occur during normal aging. Shifts in the ratio of tau genes may be a fundamental mechanism whereby normal tau expression is dysregulated, leading to NFT formation.…”