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.

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 (E10Ϫ) 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.

Aggregated tau proteins constitute the basic matrix of neuronal inclusions specific to numerous neurodegenerative disorders. Monodimensional and two-dimensional Western blot analyses performed on cortical brain homogenates allowed discrimination between disease-specific tau protein profiles. These observations raised the issue of the physiopathological significance of such specificities. Alzheimer's disease (AD) pathological tau proteins (PTPs) (tau 74, 69, 64, 55) were compared with those of Pick's disease (PiD) (tau 64, 55) using a panel of antibodies against peptidic sequences of tau isoforms corresponding to exons 2, 3, and 10. AD and PiD could then be critically differentiated by the absence of translated tau isoforms with exon 10 in PiD PTPs, along with the absence of the phosphorylation site on Ser262. Immunohistochemical studies corroborate these findings. Indeed, Pick bodies were strongly immunostained by an anti-"exon 2" antibody but failed to reveal any anti-exon 10 reactive epitope. Tangles in AD contained exon 2, 3, and 10 epitopes. Altogether, our results demonstrated that Pick bodies develop within specific neuronal subsets that express specific patterns of 7 isoforms lacking exon 10 peptidic sequence. We conclude that neurodegenerative disorders imply attrition of selectively vulnerable neuronal subsets, a process revealed, and may be sustained by specific tau isoform patterns.

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Tau proteins are the basic components of filaments that accumulate within neurons during neurofibrillary degeneration, a degenerating process with disease-specific phenotypes. This specificity is likely to be sustained by both phosphorylation state and isoform content of tau aggregates that form neuronal inclusions. In the present study, characterization of tau isoforms involved in neurofibrillary degeneration in Alzbeimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy was performed. Both analyses by immunoblotting using specific tau antibodies and cell transfection by tau isoform cDNAs allowed us to demonstrate the aggregation of (1) the six hyperpbosphorylated tau isoforms in Alzheimer's disease, (2) tau isoforms without exon 10-encoding sequence in Pick's disease and (3) hyperphosphorylated exon 10-tau isoforms in corticobasal degeneration and progressive supranuclear palsy. Thus, neurofibrillary degeneration phenotypes are likely to be related to the phosphorylation of different combinations of tau isoforms (with and/or without exon 10-encoding sequence) in subpopulations of neurons.