Apoptotic effect of caspase-3 cleaved tau in hippocampal neurons and its potentiation by tau FTDP-mutation N279K.
Pathological changes in the microtubule associated protein tau are a major hallmark of many human dementias collectively defined as tauopathies. In familiar frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), several mutations in the tau gene have been identified showing that primary malfunction of tau can lead to neurodegeneration. In addition to mutation at genetic level, a number of post-translational modifications of tau occur in tauopathies, including abnormal phosphorylation and aberrant proteolysis described in Alzheimer's Disease (AD). The presence of cleaved tau in AD neurons is associated with expression of markers for neuronal death. According to our previous work, tau is a substrate for the apoptotic protease caspase-3 that turns tau itself into an effector of apoptosis (tau cleaved at D-421), generating a positive-feedback loop that is self-propagating. Cleavage of tau by caspase-3 was recently confirmed to occur in AD brain as an early event. Here we show the apoptotic properties of tau fragment tau151-421 in primary cultures of rat hippocampal neurons; such cellular model is of special interest considering the selective vulnerability of hippocampal neurones in AD. The apoptotic capacity of tau151-421 is markedly enhanced by both treatment with amyloid peptide Abeta25-35, and the FTDP-17 tau mutation N279K.
Fasulo
Luisa
L
Laboratory Molecular Neurobiology (LMN), International School for Advanced Studies (S.I.S.S.A.), Area Science Park, Padriciano 99, 34013 Trieste, Italy.
Ugolini
Gabriele
G
Cattaneo
Antonino
A
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D003704:Dementia / Q000235:genetics* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D016875:tau Proteins / Q000502:physiology*
D017931:DNA Primers; C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases