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.

Fibroblast growth factor-2 (FGF-2) interacts with a dual receptor system consisting of tyrosine kinase receptors and heparan sulfate proteoglycans (HSPGs). In rat mammary fibroblasts, FGF-2 stimulated DNA synthesis and induced a sustained phosphorylation of p42/ 44 MAPK Fibroblast growth factor-2 (FGF-2, 1 basic FGF) possesses a dual receptor system consisting of tyrosine kinase receptors (FGF receptors (FGFRs)) (1) and heparan sulfate (HS) proteoglycans (HSPGs) (2). The interaction of FGF-2 with HS is required for the stimulation of cell proliferation (3, 4) and depends on specific patterns of sulfation of the polysaccharide (5). The interaction of FGF-2 with the FGFR is thought to induce receptor dimerization and activation of the FGFR tyrosine kinase (6 -9), which then phosphorylates a series of targets. The latter activate downstream signaling pathways, including those of the mitogen-activated protein kinases (MAPKs). The activation of two members of the MAPK family, ERK1 and ERK2, also called p44 and p42, respectively, occurs via phosphorylation by a cytoplasmic dual-specificity MAPK kinase, MEK1, and is often associated with the stimulation of cell proliferation (10 -12). The activated p42/44 MAPK will, in turn, phosphorylate an array of cellular substrates, including downstream Ser/Thr effector kinases such as p90 RSK (protein of 90 kDa from the ribosomal subunit S6 kinase gene), also known as RSK1 (12-15). p42/44 MAPK and p90 RSK also phosphorylate and activate nuclear transcription factors, e.g. c-Fos (12, 16), and enable the translocation of cytoplasmic transcription factors such as NF-B from the cytoplasm to the nucleus (12, 17). NF-B was first identified as a family of transcription factors that are activated by various stimuli such as cytokines (18,19) or growth factors, including 21). In unstimulated cells, inactive NF-B dimers are retained in the cytoplasm by interaction with the IB inhibitory proteins. Following cell stimulation, IB proteins are phosphorylated, ubiquitinated, and degraded by the 26 S proteasome (18,22). Consequently, liberated NF-B dimers are translocated to the nucleus, where they will regulate the transcription of specific target genes (12,18,23). Kinases responsible for the phosphorylation of the N terminus of IB proteins include the IB kinase complex (24 -26), casein kinase II (27, 28), and p90 RSK (29,30). Recently, the activation of p90 RSK was shown to mediate the inactivation of IB and the subsequent activation of NF-B in response to phorbol ester (30) and p53-induced cell death (17).Although the dependence of FGF-2-stimulated cell proliferation on particular structures in HS is well established (2, 5), it has become apparent that FGF-2 can interact with the FGFR in the absence of HS (31-34). A question raised by these results is whether, in the absence of its HS receptor, FGF-2 is able to stimulate all immediate-early signaling pathways or whether there are quantitative and qualitative differences in the early signals generated by FGF-2 in the absence and presence of i...

Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with a significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model.

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