Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy.
Recent evidence has suggested that truncation of tau protein at the caspase cleavage site D421 precedes hyperphosphorylation and may be necessary for the assembly of tau into filaments in Alzheimer's disease and other tauopathies. Here we have investigated the time course of the appearance of phosphorylated and truncated tau in the brain and spinal cord of mice transgenic for mutant human P301S tau protein. This mouse line recapitulates the essential molecular and cellular features of the human tauopathies, including tau hyperphosphorylation, tau filament formation, and neurodegeneration. Soluble tau was strongly phosphorylated at 1 to 6 months of age. Low levels of phosphorylated, sarkosyl-insoluble tau were detected at 2 months, with a steady increase up to 6 months of age. Tau truncated at D421 was detected at low levels in Tris-soluble and detergent-soluble tau at 3 to 6 months of age. By immunoblotting, it was not detected in sarkosyl-insoluble tau. However, by immunoelectron microscopy, a small percentage of tau in filaments from brain and spinal cord of transgenic mice was truncated at D421. Similar findings were obtained using dispersed filaments from Alzheimer's disease and FTDP-17 brains. The late appearance and low abundance of tau ending at D421 indicate that it is unlikely that truncation at this site is necessary for the assembly of tau into filaments.
Delobel
Patrice
P
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 OQH, UK.
Lavenir
Isabelle
I
Fraser
Graham
G
Ingram
Esther
E
Holzer
Max
M
Ghetti
Bernardino
B
Spillantini
Maria Grazia
MG
Crowther
R Anthony
RA
Goedert
Michel
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D010766:Phosphorylation; D013116:Spinal Cord / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D016875:tau Proteins / Q000737:chemistry*
D003902:Detergents; D016875:tau Proteins; D020169:Caspases