In tauopathies other than AD, abnormally and hyper phosphorylated tau protein aggregates are observed in the absence of amyloid deposits. Since tau aggregates differ in both degree of phosphorylation and content of tau iso forms, a molecular classification (depending on the molecular masses of the tau aggregates) into five classes has been proposed for the tauopathies (Fig.3) [13,21].

Class 0: No Tau Aggregates. After AD, frontal lobe degeneration is the second most common pre senile dementia disorder in Europe [21]. It has a frontal pathology, like Pick’s disease, but no specific neuropathological hallmark. Morphological changes comprise neuronal cell loss, spongiosis and gliosis, mainly in the superficial cortical layers of the frontal and temporal cortex. No tau aggregates are observed although loss of tau protein expression is demonstrated in this disorder, also named DLDH (dementia lacking distinctive histopathological) [21].

Class 1: A Major Tau Triplet of 60, 64, 69 kDa. This class is characterized by a pathological tau triplet of isoform of 60, 64, and 69 kDa and a minor pathological tau of 72/74 kDa. This tau isoform triplet arises from aggregation among the six tau isoforms [1,12,21]. Thus, tau 60 is composed of the shortest tau isoform, and tau 64 and 69 are mixtures of tau isoforms with exon 10 or exon 2 alone, and exon2+10+ or exon2+3+, respectively. The longest tau isoform including exon 2+3+10+ constitutes the 72/74 kDa component. The prototypical neurode generative disorder that characterizes this class is AD, but this class also includes FTDP-17, ALS/PDC of Guam, postencephalitic parkinsonism, Down’s syndrome and NPC [1,21]. Class 2: A Major Tau Doublet of 64 and 69 kDa. This class is characterized by aggregation of 4R-tau iso form and is observed in PSP, CBD and FTDP-17. In both PSP and CBD, the pathological tau profile consists of the aggregation of 4R-tau isoforms, although a study of a large series of PSP

patients revealed that the pathological tau profile is heterogeneous and includes variable amounts of 3Rtau isoforms [21]. Thus, an increased ratio of 4R/3R tau isoform is considered to define this class of tauopathies [11,13,21].

Class 3: A Major Tau Doublet of 60 and 64 kDa. In all cases of Pick’s disease, the disorder characteristic of class 3, a major 60 and 64 kDa tau doublet is observed. The tau profile of Pick’s disease is the opposite of that of class 2. The pathological isoforms consist of the 3R-tau isoforms [21].

Class 4: A Major Tau of 60 kDa. This class consists only of DM type 1 (DM1). The tau profile of DM1 is characterized by a strong tau band of 60 kDa and to a lesser extent, of isoforms of 64 and 69 kDa [21]. This profile reflects a reduced number of isoforms expressed in the brain of DM1 patients, at both the protein and the mRNA levels. Using specific immunological probes against amino acid sequences in exon 2 and exon 3, the neurofibrillary lesions were shown to be devoid of tau isoforms with amino-terminal inserts [1,21]. An altered splicing of tau gene transcript is considered to be the cause, although the mechanism remains to be established. This demonstrates that the central nervous system is affected in DM1, making this a real tauopathy [21].

Figure 3. Electrophoretic profiles of pathological tau proteins with their molecular masses (kDa), and classification of several tauopathies. Isoforms 10+: isoforms containing exon 10; isoforms 10–: isoforms without exon 10 [1].