The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy

Abstract

We report a case of rapidly progressive frontotemporal dementia presenting at age 33 years. At autopsy there was severe atrophy of the frontal and temporal lobes. Tau-positive Pick bodies, which ultrastructurally were composed of straight filaments, were present, accompanied by severe neuronal loss and gliosis. RD3, a tau antibody specific for the three-repeat (3R) isoforms, labeled the Pick bodies. ET3, a four-repeat (4R) isoform-specific tau antibody, did not label Pick bodies, but highlighted rare astrocytes, and threads in white matter bundles in the corpus striatum. Analysis of the tau gene revealed an L266V mutation in exon 9. Analysis of brain tissue from this case revealed elevated levels of exon 10+ tau RNA and soluble 4R tau. However, both 3R and 4R isoforms were present in sarkosyl-insoluble tau fractions with a predominance of the shortest 3R isoform. The L266V mutation is associated with decreased rate and extent of tau-induced microtubule assembly, and a 3R isoform-specific increase in tau self assembly as measured by an in vitro assay. Combined, these data indicate that L266V is a pathogenic tau mutation that is associated with Pick-like pathology. In addition, the results of the RD3 and ET3 immunostains clearly explain for the first time the presence of both 3R and 4R tau isoforms in preparations of insoluble tau from some Pick's disease cases.

Semi-Automated Digital Image Analysis of Pick’s Disease and TDP-43 Proteinopathy

“…We selected cases with a clinical diagnosis of bvFTD and a primary neuropathological diagnosis of PiD (n=11) or FTLD-TDPC (n=10) and normal controls with a neuropathological diagnosis of unremarkable adult brain (n=5) ( Table 1). Genetic screening for C9orf72, GRN, and MAPT mutations, as reported elsewhere (Irwin et al 2013a;Irwin et al 2013b), revealed that one PiD case had a pathogenic mutation in MAPT gene (p.Leu266Val) that was associated with PBs composed of 3R isoforms of tau with the same morphology as in sporadic disease (Hogg et al 2003). Further, one additional case harbored a C9orf72 repeat expansion (i.e.…”

Development of a sensitive ELISA for quantification of three- and four-repeat tau isoforms in tauopathies

“…We had previously developed two monoclonal antibodies; RD3 and RD4, specific for 3R-and 4R-tau isoforms, respectively and these antibodies have now been extensively utilised in several neuropathological studies (de Silva et al, 2003Hogg et al, 2003;Kitamura et al, 2005;Togo et al, 2002). In this paper, we describe the development of the first sandwich ELISAs to quantify 3R-and 4R-tau, using these antibodies.…”

Tau in Oligodendrocytes Takes Neurons in Sickness and in Health

“…The importance of tau in human OLGs has been largely obtained from studying CNS degenerative diseases [37,38,39,40,41,42,43]. Immunohistochemical staining of OLGs in selected tauopathies reveals (in OLGs) ~14 nm diameter tubules in perikarya (coiled bodies) and outer loop processes of myelin sheath (argyrophilic threads) [37,40].…”