TAU INHIBITS TUBULIN OLIGOMERIZATION

Tau Inhibits Tubulin Oligomerization induced by Prion Protein



Tau Inhibits Tubulin Oligomerization induced by Prion Protein

The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention.

Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway (Osiecka, 2011, 53).

This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

The major biological functions of the microtubule-associated protein tau, include: microtubule assembly, axonal transport, neurite outgrowth, and stability of microtubules. Most of the biological functions of tau are modulated by site-specific phosphorylation. Tau self-assembly, aggregation, and accumulation in neurofibrillary tangles (NFTs) are hallmarks of Alzheimer's disease (AD) and other neurodegenerative diseases. Although the importance of tau in AD and other tauopathies is well-established, unanswered is whether NFTs are the primary neurotoxic factor. Most research has focused on NFTs because of the reported correlation between NFTs and disease progression in the brains of AD patients. However, recent data suggest that soluble pre-filament forms of tau may be the most toxic and pathologically significant forms of tau aggregates. Cell death and synaptic lesions occur independently of formation of NFTs in ...