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Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau delta K280

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Mandelkow,  Eckhard
Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Mandelkow,  Eva-Maria
Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Citation

Dennissen, F. J. A., Anglada-Huguet, M., Sydow, A., Mandelkow, E., & Mandelkow, E.-M. (2016). Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau delta K280. Proceedings of the National Academy of Sciences of the United States of America, 113(41), 11597-11602. doi:doi: 10.1073/pnas.1603119113.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-8D9D-2
Abstract
Accumulation of Tau is a characteristic hallmark of several neurodegenerative diseases but the mode of toxic action of Tau is poorly understood. Here, we show that the Tau protein is toxic due to its aggregation propensity, whereas phosphorylation and/or missorting is not sufficient to cause neuronal dysfunction. Aggregate-prone Tau accumulates, when expressed in vitro at near-endogenous levels, in axons as spindle-shaped grains. These axonal grains contain Tau that is folded in a pathological (MC-1) conformation. Proaggregant Tau induces a reduction of neuronal ATP, concomitant with loss of dendritic spines. Counterintuitively, axonal grains of Tau are not targeted for degradation and do not induce a molecular stress response. Proaggregant Tau causes neuronal and astrocytic hypoactivity and presynaptic dysfunction instead. Here, we show that the adenosine A1 receptor antagonist rolofylline (KW-3902) is alleviating the presynaptic dysfunction and restores neuronal activity as well as dendritic spine levels in vitro. Oral administration of rolofylline for 2-wk to 14-mo-old proaggregant Tau transgenic mice restores the spatial memory deficits and normalizes the basic synaptic transmission. These findings make rolofylline an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases.