Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280
| Autor: | Marta Anglada-Huguet, Eva-Maria Mandelkow, Frank J.A. Dennissen, Astrid Sydow, Eckhard Mandelkow |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
pathology [Tauopathies] Dendritic spine pharmacology [Xanthines] rolofylline Fluorescent Antibody Technique Gene Expression metabolism [Hippocampus] metabolism [Axons] Hippocampus Synaptic Transmission Rolofylline chemistry.chemical_compound Mice 0302 clinical medicine Adenosine Triphosphate Premovement neuronal activity pathology [Neurons] drug therapy [Tauopathies] Phosphorylation Sequence Deletion Neurons drug effects [Synaptic Transmission] Multidisciplinary biology drug effects [Memory Long-Term] Biological Sciences Mitochondria Tauopathies metabolism [Neurons] ddc:500 Genetically modified mouse Memory Long-Term Dendritic Spines Tau protein Mice Transgenic tau Proteins Neurotransmission Adenosine A1 Receptor Antagonists Protein Aggregation Pathological 03 medical and health sciences Adenosine A1 receptor Protein Aggregates metabolism [Protein Aggregation Pathological] mental disorders genetics [Protein Aggregation Pathological] Animals Humans drug effects [Dendritic Spines] Antagonist genetics [Tauopathies] metabolism [Mitochondria] Axons genetics [tau Proteins] Disease Models Animal 030104 developmental biology pathology [Hippocampus] chemistry metabolism [Adenosine Triphosphate] Xanthines biology.protein metabolism [Tauopathies] Neuroscience pharmacology [Adenosine A1 Receptor Antagonists] 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America 113(41), 11597-11602 (2016). doi:10.1073/pnas.1603119113 Proceedings of the National Academy of Sciences of the United States of America |
| DOI: | 10.1073/pnas.1603119113 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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