TDP-43 pathology may occur in the BRI2 gene-related dementias

Abstract

The ubiquitously expressed TAR DNA-binding protein-43 (TDP-43), involved in transcription and alternative splicing, is a major disease protein in frontotemporal lobar degeneration and amyotrophic lateral sclerosis [8]. TDP43-positive inclusions may also be detected in other neurodegenerative diseases, including Alzheimer’s disease (AD), Lewy body disorders, corticobasal degeneration and the parkinsonism–dementia complex of Guam (PDCG) [8]. In 2009, Schwab et al. [12] reported TDP-43 pathology including neuronal cytoplasmic inclusions (NCIs), dystrophic neurites and occasional positivity in neurofibrillary tangle (NFT) fibres in a case with familial British dementia (FBD). FBD and familial Danish dementia (FDD), also known as BRI2 gene-related dementias [3], are inherited cerebral amyloid diseases, in which the relevant 34 aminoacid-long amyloid peptides, ABri in FBD and ADan in FDD, are cleaved from the C-terminus of the mutated BRI2 precursor proteins [13, 14]. Although ABri and ADan show no homology to amyloid-beta, the neuropathology of FBD and FDD with amyloid and diffuse plaques, cerebral amyloid angiopathy and NFT pathology [5, 6] is remarkably similar to that of AD. As the study of Schwab et al. [12] investigated one case, the frequency of TDP-43 pathology in FBD remains unknown. This prompted us to screen sections of formalinfixed, paraffin embedded tissue from the hippocampal formation, temporal and frontal cortex and amygdala for TDP-43 pathology in five FBD and four FDD cases (mean age at death 62.2 and 53.5 years, respectively), using two non-phosphorylation dependent (Abnova, ProteinTech) and one phosphorylation dependent (pS409/410; Cosmo Bio Co.) antibodies. We found rare TDP-43-positive NCIs in the CA1 hippocampal subregion in one of the FBD cases (Fig. 1), but all the FDD cases were negative. TDP-43 pathology, most commonly in a limbic distribution, is relatively frequent in AD, although a ‘diffuse type’ with widespread TDP-43 inclusions is also known [1]. TDP-43 pathology may be present in up to 60% of the AD cases when pTDP-43 antibodies are used and the amygdala is also screened [2]. Similar to the majority of AD cases, the TDP-43 pathology showed a limbic distribution in the FBD case reported by Schwab et al. [12] and the rare TDP-43-positive NCIs were found in the hippocampus in one of our five FBD cases, supporting the notion that mesial temporal lobe structures are particularly susceptible to TDP-43 pathology [2]. Although we have investigated the largest available cohort of cases, it is not possible to accurately estimate the frequency of associated TDP-43 pathology in FBD. If data from the study of Schwab et al. [12] and from our study are pooled (six cases), one can estimate that up to one-third of the FBD cases may have at least some TDP-43 pathology. No such pathology has so far been observed in FDD. The cause and mechanism of TDP-43 proteinopathies occurring in association with a number of neurodegenerative diseases is unknown [8]. As in AD, tau pathology is severe and the amyloid plaque load is high in limbic structures in FBD, which could indicate that similar cellular mechanisms are involved in initiating neurodegeneration including TDP-43 pathology in both AD and FBD. Our observation of TDP-43 inclusions in the hippocampal formation affected by prion amyloid plaques and extensive NFT pathology in hereditary prion disease with Y163X T. Lashley J. L. Holton T. Revesz (&) Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK e-mail: T.Revesz@ion.ucl.ac.uk