Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280.
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 A1receptor 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.
German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Center of Advanced European Studies and Research, 53175 Bonn, Germany; frank.dennissen@DZNE.de eva.mandelkow@dzne.de.
Frank J A
FJ
Dennissen
German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Max Planck Institute for Metabolism Research, 22607 Hamburg, Germany.
Marta
M
Anglada-Huguet
German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Max Planck Institute for Metabolism Research, 22607 Hamburg, Germany.
Astrid
A
Sydow
German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Center of Advanced European Studies and Research, 53175 Bonn, Germany; Max Planck Institute for Metabolism Research, 22607 Hamburg, Germany.
Eckhard
E
Mandelkow
German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Center of Advanced European Studies and Research, 53175 Bonn, Germany; Max Planck Institute for Metabolism Research, 22607 Hamburg, Germany frank.dennissen@DZNE.de eva.mandelkow@dzne.de.
Eva-Maria
EM
Mandelkow
D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057567:Memory, Long-Term / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D009435:Synaptic Transmission / Q000187:drug effects; D024801:Tauopathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014970:Xanthines / Q000494:pharmacology*; D016875:tau Proteins / Q000235:genetics*
D058916:Adenosine A1 Receptor Antagonists; D066329:Protein Aggregates; D014970:Xanthines; D016875:tau Proteins; C073525:rolofylline; D000255:Adenosine Triphosphate
axons; hypoactivity; rolofylline; tauopathies; treatment
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