Adenosine A^sub 1^ receptor antagonist rolofylline alleviates axonopathy caused by human Tau [delta]K280

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 neurona...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2016-10, Vol.113 (41), p.11597
Main Authors: Dennissen, Frank J A, Anglada-Huguet, Marta, Sydow, Astrid, Mandelkow, Eckhard, Mandelkow, Eva-Maria
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Language:English
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Adenosine triphosphatase
Memory
Metabolism
Neurons
Proteins
Rodents
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Anglada-Huguet, Marta
Sydow, Astrid
Mandelkow, Eckhard
Mandelkow, Eva-Maria
description 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.
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source JSTOR Archival Journals and Primary Sources Collection【Remote access available】; PubMed Central
subjects Adenosine triphosphatase
Memory
Metabolism
Neurons
Proteins
Rodents
title Adenosine A^sub 1^ receptor antagonist rolofylline alleviates axonopathy caused by human Tau [delta]K280
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