Neuron-specific suppression of aberrantly active Toll-NFκB signalling mitigates pathogenic tau hyperphosphorylation...

Chronic brain ailments like Alzheimer's disease and Frontotemporal dementia, together referred to as tauopathies, are strongly influenced by neuroinflammation, an age-associated functional anomaly. Neuroinflammation arising from a dysfunctional innate immune response, such as Toll-NFκB signalling, is implicated in modulating tau pathophysiology, with limited understanding of the molecular mechanisms. Pathogenic hyperphosphorylation of tau and its aggregation into neurotoxic species is considered as a central trigger of tau pathology; however, the mechanistic association between these pathogenic events and the Toll signalling remains largely unexplored. We examined the status of the Toll signalling in Drosophila tauopathy models and evaluated whether its modulation modifies disease severity. We present compelling evidence that neuronal expression of pathogenic human tau causes aberrant activation of the Toll signalling. In line, its additional upregulation further aggravates disease severity, while genetic downregulation of Toll components remarkably alleviates both structural and functional deficits. We subsequently noted that knockdown of the Toll pathway attenuates pathogenic tau hyperphosphorylation in a site-specific manner, largely coinciding with restoration of physiological activity of Gsk-3β/Akt/PP2Ac signalling, a relatively less explored molecular axis in neurons. Our study posits a potential contribution of neuron-intrinsic altered Toll signalling cascade in tau pathogenesis, warranting further exploration of this evolutionarily conserved pathway as a therapeutic target.