Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

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 A 1 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.tauopathies | rolofylline | hypoactivity | axons | treatment

Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage

“…Extracellular tau is implicated as the primary agent during propagation of neurofibrillary lesions and spreading of tau toxicity (Medina and Avila, 2014). In trans-synaptic propagation, tau can be released and taken up by a synaptically-connected neuron (Clavaguera et al, 2009; Dujardin et al, 2014b; Dennissen et al, 2016). A recent study showed that neuronal networks facilitate cell-to-cell transfer of tau via synapses; using a microfluidic device they demonstrated that decreasing synaptic connections weakens tau transfer and the subsequent aggregation on the acceptor cell (Calafate et al, 2015).…”

Interplay of pathogenic forms of human tau with different autophagic pathways

“…Although tauopathies are caused by mutations in the same protein, tau, different types of tauopathies appear to affect different brain regions and exhibit distinct symptoms, suggesting that tau mutations may have distinctive consequences. For instance, we recently revealed that tau mutations ΔK280 and A152T influence neuronal activity in an opposite manner (Decker et al ., 2016; Dennissen et al ., 2016). We wondered whether different tau mutations may also impact tau clearance differently.…”

Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

“…In this study the status of synaptic proteasome function and synaptic tau concentrations were not assessed, but the same improvements in synapses were seen when tau aggregation was inhibited [95]. These findings suggest that enhanced cAMP could mediate the clearance of tau by the UPS [95]. …”

“…Supporting this hypothesis, a report demonstrated in a mouse model of HD (line R6/2) that in vivo chronic stimulation of the A2A receptor resulted in a Gs-coupled response, improved proteasome function by PKA-mediated phosphorylation, and reduced HTT aggregates in striatal synapses [49]. Recently, a study in tau transgenic mice expressing the FTD mutation ΔK280 [95] demonstrated that administration of rolofylline, an antagonist of the Gi-coupled adenosine A1 receptor located on the membrane of synaptic terminals, which can lead to elevated cAMP signaling, restored neuronal activity, and prevented presynaptic impairment and dendritic spine loss [95]. In this study the status of synaptic proteasome function and synaptic tau concentrations were not assessed, but the same improvements in synapses were seen when tau aggregation was inhibited [95].…”

“…Recently, a study in tau transgenic mice expressing the FTD mutation ΔK280 [95] demonstrated that administration of rolofylline, an antagonist of the Gi-coupled adenosine A1 receptor located on the membrane of synaptic terminals, which can lead to elevated cAMP signaling, restored neuronal activity, and prevented presynaptic impairment and dendritic spine loss [95]. In this study the status of synaptic proteasome function and synaptic tau concentrations were not assessed, but the same improvements in synapses were seen when tau aggregation was inhibited [95]. These findings suggest that enhanced cAMP could mediate the clearance of tau by the UPS [95].…”