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Typing tau pathology in neurodegenerative diseases
Type I and type II biochemical signatures
Tau gene is a long 100 kb gene located on chromosome 17.
A: six different mRNAs are produced in the adult human brain, by alternative splicing.
B: consequently, six tau isoforms are expressed. Three of them have an additional repeat binding site to microtubules, corresponding to the sequence encoded by exon 10.
C (left part): Alzheimer brain lesions (tangles, neuropile threads and dystrophic neurites of neuritic plaques) are composed of the six isoforms (left part). They assemble into PHF (paired helical filaments) with a width of 8 to 20 nm and a periodicity of 80 nm.
D: the biochemical signature of PHF is a class I profile, with a major triplet of electrophoretic band (tau 60, 64, 69). C' (right part): In FTDP-17, many pathogenic mutations on tau gene provoke the aggregation of 3 tau isoforms with 4 repeats. The three 4R tau isoforms aggregate into 15 nm wide twisted filaments with a cross over spacing of 130 nm. These filaments are found in neuronal and astrocytes. D': a class II biochemical signature (a major tau 64, 69 doublet) is observed.
Type I, II, II
These biochemical signatures result from the specific aggregation of tau isoforms with or without exon 10. They have been validated on experimental models (Mailliot et al).
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