PATHOGENIC HUMAN-TAU OVEREXPRESSION IN THE SUPRACHIASMATIC NUCLEUS INDUCES DISRUPTION OF CIRCADIAN RHYTHMS AT THE BEHAVIOURAL AND MOLECULAR LEVEL

The mammalian circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus shapes daily rhythms of activity. Disruption of circadian rhythms is a frequent feature in tauopathies, a group of neurodegenerative diseases characterized by the intracellular accumulation of pathological forms of the microtubule-associated-protein-tau (MAPT). Recent studies associated Frontotemporal Dementia (FTD) diagnosis with changes in the SCN and presence of phosphorylated forms of tau. However, the mechanisms linking pathogenic tau isoforms and circadian dysfunction are unknown.
To study the effect of hTau on the SCN circuit, we used somatic viral transgenesis to express the 0N4R isoform of human-Tau (Syn-hTau^WT::FusionRed), a 0N4R isoform containing the FTD-associated P301L/S320F mutations (Syn-hTau^Mut::FusionRed), or a control construct expressing the FusionRed tag in SCN neurons. hTau accumulation in the SCN (revealed by AT8 staining) caused a reduction of period length in rest-activity cycles, which was more pronounced in the presence of FTD mutations. Ex-vivo expression of hTau in SCN organotypic slices resulted in shorter rhythms of neuronal Ca²⁺ and disruption of network activity, detected via circadian fluorescent live-imaging recordings using the ClockCyte platform. Genetic reduction of clock gene BMAL1 expression allowed us to investigate the interplay between the molecular clockwork and pathogenic tau. We observed faster rates of accumulation of hTau in presence of reduced BMAL1 expression.
These findings support a bidirectional interaction between Tau pathology and circadian function: Tau accumulation induces specific disruptions of circadian circuitry and rest-activity rhythms, while impairment of the molecular clockwork, via reduced BMAL1 expression, accelerates the progression of hTau pathology.