Brain Pathology, Volume 9 Number 4 October 1999

Comparative Biochemistry of Tau in Progressive Supranuclear Palsy, Corticobasal Degeneration, FTDP-17 and Pick's Disease

Luc Buée and André Delacourte

INSERM U422, F-59045 Lille, France

Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau60, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R-tau isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R-tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto-temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrukimental in many neurodegenerative disorders.

The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease

A. Delacourte PhD; J. P. David MD; N. Sergeant PhD; L. Buée PhD; A. Wattez BSc; P. Vermersch MD, PhD; F. Ghozali MD; C. Fallet-Bianco MD; F. Pasquier MD, PhD; F. Lebert MD; H. Petit MD; C. Di Menza MD

Neurology 1999;52:1158 

Objective: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. Background: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. Methods: The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and A were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. Results: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired. Conclusions: The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.

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(Choose Neurology, then Content, then Volume 52, issue April 12,1999)

J Neurochem 1999 Mar;72(3):1243-9

Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively "exon 10" isoforms.

Sergeant N, Wattez A, Delacourte A

INSERM Unite 422, Lille, France.

Pathological tau proteins that constitute the basic matrix of neuronal inclusions observed in numerous neurodegenerative disorders are disease specific. This is mainly the consequence of the aggregation of specific sets of tau isoforms according to the diseases, i.e., six isoforms in Alzheimer's disease (AD) and exclusively the three tau isoforms lacking the corresponding sequence of exon 10 (E10-) in Pick's disease (PiD). By using antibodies specific to the different tau isoforms and one- and two-dimensional gel electrophoresis followed by western blots, we demonstrate herein a third group of neurodegenerative disorders characterized by intraneuronal inclusions exclusively constituted of tau isoforms containing the sequence corresponding to exon 10, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Together, tau isoforms with exon 10 clearly differentiate three groups of neurodegenerative diseases: AD, PiD, and PSP/CBD. For each group, the neuropathological and clinical phenotypes are most likely related to specific sets of tau isoforms expressed by the vulnerable neuronal populations. The recently described mutations of the tau gene responsible for familial frontotemporal dementias also support this hypothesis.

Neuroreport 1999 Feb 25;10(3):487-91

A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form.

Brique S, Destee A, Lambert JC, Mouroux V, Delacourte A, Amouyel P, Chartier-Harlin MC

Department of Neurology A, Hopital Roger Salengro, Centre Hospitalier Universitaire, Lille, France.

We found a new mutation in the GTP cyclohydrolase gene involved in dopa-responsive dystonia. We sequenced the GTP cyclohydrolase gene in a family with four siblings affected by this disorder and identified an A-T mutation in exon 2, leading to a non conservative amino acid substitution at codon 135 of the protein (Ile135Lys), which may change the conformation of the binding site of this enzyme. The clinical evolution was heterogeneous among carriers of the same mutation, underlining the involvement of other determinants modulating the occurrence of the disease such as genetic or environmental susceptibility factors.

Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration.

Bussiere T, Hof PR, Mailliot C, Brown CD, Caillet-Boudin ML, Perl DP, Buee L, Delacourte A

INSERM U 422, Place de Verdun, F-59045 Lille, France.

Neuronal inclusions with bundles of abnormal filaments made of tau polymers are found in numerous diseases with neurofibrillary degeneration. Tau proteins are the basic components of paired helical filaments (PHF) in Alzheimer's disease (AD), and are abnormally phosphorylated. A disease-specific phosphorylation site at serine422 was demonstrated on PHF, but not on tau proteins from biopsy-derived brain samples. In the present study, we report the characterization of a polyclonal antibody (988) against the serine422 phosphorylation site. By using biochemical and immunohistochemical methods, we confirmed that it is not found on tau proteins from biopsy- or autopsy-derived control samples, and we investigated the presence of this epitope on tau proteins in several neurodegenerative disorders, including AD, Down syndrome (DS), Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), postencephalitic parkinsonism (PEP) and Pick's disease (PiD). By Western blotting, antibody 988 labeled the characteristic tau triplet (tau 55, 64, 69) in AD, DS, Guamanian ALS/PDC and PEP. PSP and CBD exhibited their typical tau doublet (tau 64, 69), whereas the doublet tau 55 and 64 was detected in PiD. In all of these neurodegenerative disorders, antibody 988 clearly labeled NFT and dystrophic neurites, as well as Pick bodies in PiD cases, whereas no staining was observed in control cases. These data indicate that phosphorylation of serine422 on tau proteins is a common feature among neurodegenerative disorders and is therefore not specific of AD. Moreover, phosphorylation of this epitope permits the distinction between normal tau proteins and pathological tau proteins.

Pérez-Tur J, Buée L, Morris H, Waring S, Onstead L, Wavrant-De Vrièze F, Crook R, Buée-Scherrer V, Hof PR, Perl DP, Petersen R, McGeer P, Delacourte A, Hutton M, Siddique T, Ahlskog EJ, Hardy J, Steele J. Absence of mutations in the TAU gene in Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex of Guam. Neurology, 1999, 53:411-413

Sato N, Hori O, Yamaguchi 0, Lambert JC, Chartier-Harlin M-C, Robinson PA, Delacourte A, Schmidt AM, Furuyama T, Imaizumi K, Tohyama M, Takagi T. A Novel Presenilin-2 Splice Variant in Human Alzheimer's Disease Brain Tissue. J. Neurochem. (1999) 72:2498-2505

Delacourte A. Biochemical and molecular characterization of neurofibrillary degeneration in frontotemporal dementias. Dement Geriatr Cogn Disord, 1999;10(suppl 1) 75-79

Soulié C, Mitchell V, Dupont-Wallois L, Chartier-Harlin MC, Beauvillain JC, Delacourte A, Caillet-Boudin ML. Synthesis of apolipoprotein E (ApoE) mRNA by human neuronal type SKNSH-SY5Y cells and its regulation by nerve growth factor and ApoE. Neurosci Lett 1999, 265(2):147-50.

Wavrant- De Vrièze F, Pasquier F, Delacourte A, Frigard B, Amouyel P, Hardy J, Chartier-Harlin MC, Pérez-Tur J. Genetic risk factors for late-onset Alzheimer's disease. Annals of Psychiatry. 1999, 7:19-27