Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep

Abstract

Multiple neurological, physiological, and behavioral functions are synchronized by circadian clocks into daily rhythms. Neurodegenerative diseases such as Alzheimer’s disease and related tauopathies are associated with a decay of circadian rhythms, disruption of sleep patterns, and impaired cognitive function but the mechanisms underlying these alterations are still unclear. Traditional approaches in neurodegeneration research have focused on understanding how pathology impinges on circadian function. Since in Alzheimer’s disease and related tauopathies tau proteostasis is compromised, here we sought to understand the role of tau protein in neuronal circadian biology and related behavior. Considering molecular mechanisms underlying circadian rhythms are conserved from Drosophila to humans, here we took advantage of a recently developed tau-deficient Drosophila line to show that loss of tau promotes dysregulation of daily circadian rhythms and sleep patterns. Strikingly, tau deficiency dysregulates the structural plasticity of the small ventral lateral circadian pacemaker neurons by disrupting the temporal cytoskeletal remodeling of its dorsal axonal projections and by inducing a slight increase in the cytoplasmic accumulation of core clock proteins. Taken together, these results suggest that loss of tau function participates in the regulation of circadian rhythms by modulating the correct operation and connectivity of core circadian networks and related behavior.

Disease-Associated Mutant Tau Prevents Circadian Changes in the Cytoskeleton of Central Pacemaker Neurons

“…That hTau WT /CS also showed changes in the sleep pattern may be due to it not being completely able to substitute for Drosophila dTau. This is supported by the recent finding that the loss of dTau reduces sleep and increases activity (Arnes et al, 2019). Furthermore, we found that also haploinsufficiency by using a dTau knock-out-line (Burnouf et al, 2016), impaired the sleep pattern (Supplementary Figure S3C) and induced hyperactivity when tested at 5-day ( Supplementary Figure S3D).…”

Better Sleep at Night: How Light Influences Sleep in Drosophila

“…dTau null flies exhibit a significant reduction in the structural morphology of the s-LNv at ZT2 compared to wt, in line with the behavioural defects (increased activity and decreased sleep) displayed in the early day (Arnes et al, 2019). Furthermore, in s-LNvs, dTau shows rhythmic expression at both mRNA and protein levels, with significantly higher levels in the early morning (ZT2) than in the early night (Abruzzi et al, 2017;Arnes et al, 2019). This temporal rhythmic pattern perfectly matches with its role in modulating the structural plasticity of s-LNvs terminals (Arnes et al, 2019).…”

“…At the neuronal level, dTau plays an essential role in modulating the structural plasticity of s-LNvs terminals: in wt flies the dorsal projections of s-LNvs neurons display a rhythmic remodeling, with significantly higher degree of axonal arborisation in the early day (ZT2) compared to early night (ZT14) (Fernández et al, 2008). dTau null flies exhibit a significant reduction in the structural morphology of the s-LNv at ZT2 compared to wt, in line with the behavioural defects (increased activity and decreased sleep) displayed in the early day (Arnes et al, 2019). Furthermore, in s-LNvs, dTau shows rhythmic expression at both mRNA and protein levels, with significantly higher levels in the early morning (ZT2) than in the early night (Abruzzi et al, 2017;Arnes et al, 2019).…”

“…Small ventral-lateral neurons express dTau, a protein with microtubule-binding properties, homolog to mammalian Tau, known to be involved in the maturation and establishment of synaptic networks regulating complex behaviours (Abruzzi et al, 2017;Tracy and Gan, 2018). dTau plays an important role in shaping behavioural rhythms and sleep patterns: in either LD cycles or DD, dTau mutant flies exhibit an increased activity during the day/subjective day, more pronounced in the middle of the day, when wt flies have a "siesta" (Arnes et al, 2019). This altered locomotor phenotype is mirrored by pronounced sleep alterations: dTau null flies exhibit a significant alteration of daytime sleep, while nocturnal sleep is not affected: the total daytime sleep is significantly decreased, including the "siesta, " the sleep episodes are shorter, that is, sleep is more fragmented, and the sleep latency is significantly longer (Arnes et al, 2019).…”

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…MAPT −/− mice also spend significantly less time in the open arms of elevated Z-mazes and keep to the periphery of open field arenas, indicative of increased anxiety [86]. Tau may also help to regulate circadian behaviours, with MAPT −/− mice [41] or Drosophila [8], showing major abnormalities in the sleep-wake cycle, including increased wakefulness and disruption to normal circadian activities. Sleep disturbances are commonly reported in ageing and neurodegenerative disorders [281], so understanding how tau alterations impact sleep may be clinically relevant.…”