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Development and assessment of sensitive immuno-PCR assays for the quantification of cerebrospinal fluid three- and four-repeat tau isoforms in tauopathies

Journal article
Authors C. Luk
Y. Compta
N. Magdalinou
M. J. Marti
G. Hondhamuni
Henrik Zetterberg
Kaj Blennow
Radu Constantinescu
Y. Pijnenburg
B. Mollenhauer
C. Trenkwalder
J. Van Swieten
W. Z. Chiu
B. Borroni
A. Camara
P. Cheshire
D. R. Williams
A. J. Lees
R. de Silva
Published in Journal of Neurochemistry
Volume 123
Issue 3
Pages 396-405
ISSN 0022-3042
Publication year 2012
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 396-405
Language en
Links dx.doi.org/10.1111/j.1471-4159.2012...
Keywords biomarkers, CSF, MAPT, tau, tauopathy, progressive supranuclear palsy, corticobasal degeneration, parkinsons-disease, alzheimers-disease, in-vitro, neuropathologic, criteria, alpha-synuclein, psp brain, dementia, accuracy, lstein mf, 1975, journal of psychiatric research, v12, p189
Subject categories Neurosciences, Medical Biotechnology

Abstract

Characteristic tau isoform composition of the insoluble fibrillar tau inclusions define tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal dementia with parkinsonism linked to chromosome 17/frontotemporal lobar degeneration-tau (FTDP-17/FTLD-tau). Exon 10 splicing mutations in the tau gene, MAPT, in familial FTDP-17 cause elevation of tau isoforms with four microtubule-binding repeat domains (4R-tau) compared to those with three repeats (3R-tau). On the basis of two well-characterised monoclonal antibodies against 3R- and 4R-tau, we developed novel, sensitive immuno-PCR assays for measuring the trace amounts of these isoforms in CSF. This was with the aim of assessing if CSF tau isoform changes reflect the pathological changes in tau isoform homeostasis in the degenerative brain and if these would be relevant for differential clinical diagnosis. Initial analysis of clinical CSF samples of PSP (n = 46), corticobasal syndrome (CBS; n = 22), AD (n = 11), Parkinson's disease with dementia (PDD; n = 16) and 35 controls revealed selective decreases of immunoreactive 4R-tau in CSF of PSP and AD patients compared with controls, and lower 4R-tau levels in AD compared with PDD. These decreases could be related to the disease-specific conformational masking of the RD4-binding epitope because of abnormal folding and/or aggregation of the 4R-tau isoforms in tauopathies or increased sequestration of the 4R-tau isoforms in brain tau pathology.

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