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.

Intraneuronal aggregates of hyperphosphorylated tau proteins, referred to as pathological tau, are found in brain areas of demented patients affected by numerous different neurodegenerative disorders. We previously described a particular biochemical profile of pathological tau proteins in myotonic dystrophy type 1 (DM1). This multisystemic disorder is characterized by an unstable CTG repeat expansion in the 3'-untranslated region of the DM protein kinase gene. In the human central nervous system, tau proteins consist of six isoforms that differ by the presence or absence of the alternatively spliced exons 2, 3 and 10. Here we show that the pattern of tau isoforms aggregated in DM1 brain lesions is characteristic. It consists mainly of the aggregation of the shortest human tau isoform. A disruption in normal tau isoform expression consisting of a reduced expression of tau isoforms containing the exon 2 was observed at both the mRNA and protein levels. Large expanded CTG repeats were detected and showed marked somatic heterogeneity between DM1 cases and in cortical brains regions analysed. Our data suggest a relationship between the CTG repeat expansion and the alteration of tau expression showing that DM1 is a peculiar tauopathy.

Vaccination against human beta-amyloid peptide (Ab) has been shown to remove the amyloid burden produced in transgenic mice overexpressing the mutated human amyloid precursor protein (APP) gene. For human beings, the efficiency of this therapeutic strategy has to take into account the specificities of human amyloid, especially at the early stages of 'sporadic' Alzheimer's disease (AD). Ab 40/42 were previously quantified in tissues from our well-established brain bank, including non-demented individuals with both mild amyloid and tau pathologies, hence corresponding to the earliest stages of Alzheimer pathology. Herein, we have adapted a proteomic method combined with western blotting and mass spectrometry for the characterization of insoluble Ab extracted in pure-formic acid. We demonstrated that amino-truncated Ab species represented more than 60% of all Ab species, not only in full blown AD, but also, and more interestingly, at the earliest stage of Alzheimer pathology. At this stage, Ab oligomers were exclusively made of Ab-42 species, most of them being amino-truncated. Thus, our results strongly suggest that amino-truncated Ab-42 species are instrumental in the amyloidosis process. In conclusion, a vaccine specifically targeting these pathological amino-truncated species of Ab-42 are likely to be doubly beneficial, by inducing the production of specific antibodies against pathological Ab products that are, in addition, involved in the early and basic mechanisms of amyloidosis in humans. Keywords: Alzheimer's disease, beta-amyloid peptide, proteomic, diagnostic, vaccination, physiopathology. Alzheimer's disease (AD) is a progressive dementing disorder characterized by the conjunction of two degenerative processes: tau pathology and amyloid pathology. Both degenerative processes are found in familial autosomal dominant AD and in 'sporadic' AD (non-mendelean). However, familial autosomal dominant AD due to mutations on amyloid precursor protein (APP) or presenilin genes are extremely rare ) and furthermore, less is known about the physiopathology of 'sporadic' AD.The cognitive decline that characterizes AD is well correlated to the cortical spreading of tau pathology (Delacourte et al. 1999). However, the amyloid pathology is in close relationship with the aetiology of the disease. We have recently shown a strong correlation between the amyloid pathology and the dynamic of progression of tau pathology in cortical brain areas, hence demonstrating a synergy between tau and amyloid pathologies in 'sporadic' AD Sergeant et al. 2002). It suggests overall that the amyloid pathology could trigger the spreading of tau pathology, thus leading to AD. This hypothesis is also illustrated in transgenic mouse models, in which the tau

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.