Anti-tau antibodies reduce tau seeding induced by pathological tau species and Alzheimer-like tauopathy in neurons

Identification: Volbracht, Christiane


Anti-tau antibodies reduce tau seeding induced by pathological tau species and Alzheimer-like tauopathy in neurons
Christiane Volbracht, Lone Helboe, Lars Østergaard Pedersen, Jeppe Falsig Pedersen, Nina Rosenqvist, Jan Torleif Pedersen
H. Lundbeck A/S, Neuroscience Drug Discovery, Neurodegeneration, Valby, Denmark
The abnormal hyperphosphorylation of the microtubule-associated protein tau plays a crucial role in neurodegeneration in Alzheimer's disease (AD) and aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs) is a hallmark in AD. The mechanisms underlying the transformation of highly soluble normal tau into insoluble NFTs remain unclear. We established an assay in primary neurons isolated from tau transgenic rTg4510 mice in which NFT-like tau aggregates develop to investigate mechanisms of tau pathogenesis and tau-based therapeutics in vitro. The rTg4510 mouse strain overexpresses an inducible human mutant P301L tau and displays age-dependent tau pathology including NFTs. Primary cortical cultures isolated from embryonic rTg4510 mice were expressing human mutant P301L tau without presenting tau pathology and were incubated with low concentrations of pathological tau species isolated from AD or aged rTg4510 brains. Sarkosyl-insoluble hyperphosphorylated tau species were spontaneously taken up by cortical neurons and initiated seeding of normal transgene human tau in rTg4510 cortical cultures over long term incubation periods. Tau seeding in neurons was characterized by recruitment of soluble endogenous tau into inclusions of aggregated and hyperphosphorylated tau displayed at higher molecular weight on SDS page recapitulating some features of Alzheimer-like tauopathy in neurons. These findings indicate that low amounts of exogenous pathological tau species can engage with normal endogenous human tau species and induce tau seeding and pathology in neurons in vitro, suggesting a seeding and recruitment process as a possible mechanism underlying NFT formation in vivo. Phosphorylation dependent and independent anti-tau antibodies binding to pathological tau did not prevent uptake of tau into neurons, were taken up together with tau into neurons and significantly reduced tau seeding and aggregation in rTg4510 cortical neurons. Our findings suggest that anti-tau antibodies can obstruct the tau seeding and aggregation process in the neurons without affecting the uptake of pathological tau.


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