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

Abstract

A hallmark feature of Alzheimer's disease (AD) and other Tauopathies, like Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), is the accumulation of neurofibrillary tangles composed of the microtubule-associated protein Tau. As in AD, symptoms of FTDP-17 include cognitive decline, neuronal degeneration, and disruptions of sleep patterns. However, mechanisms by which Tau may lead to these disturbances in sleep and activity patterns are unknown. To identify such mechanisms, we have generated novel Drosophila Tauopathy models by replacing endogenous fly dTau with normal human Tau (hTau) or the FTDP-17 causing hTau V337M mutation. This mutation is localized in one of the microtubule-binding domains of hTau and has a dominant effect. Analyzing heterozygous flies, we found that aged hTau V337M flies show neuronal degeneration and locomotion deficits when compared to wild type or hTau WT flies. Furthermore, hTau V337M flies are hyperactive and they show a fragmented sleep pattern. These changes in the sleep/activity pattern are accompanied by morphological changes in the projection pattern of the central pacemaker neurons. These neurons show daily fluctuations in their connectivity, whereby synapses are increased during the day and reduced during sleep. Synapse formation requires cytoskeletal changes that can be detected by the accumulation of the end-binding protein 1 (EB1) at the site of synapse formation. Whereas, hTau WT flies show the normal day/night changes in EB1 accumulation, hTau V337M flies do not show this fluctuation. This suggests that hTau V337M disrupts sleep patterns by interfering with the cytoskeletal changes that are required for the synaptic homeostasis of central pacemaker neurons.

The HPA Axis under Stress and Aging: Individual Vulnerability is Associated with Behavioral Patterns and Exposure Time

“…[ 23,26,41–44 ] The main role in this system is played by the SCN, which synchronizes the peripheral circadian clock network. [ 23,26,41,43,45,46 ] It has been demonstrated that SCN has a direct effect on the regulation of glucocorticoid circadian rhythms mediated by neural projections into the hypothalamic PVN. PVN, in turn, switches the light signal to the HPA axis, providing a basis for diurnal fluctuations in its activity with an increase in the concentration of circulating glucocorticoids during the active phase of the day (during the day in humans and primates and at night in nocturnal species).…”

“…It is generally accepted that, with aging, a damping of the circadian amplitude of activity of SCN oscillatory neurons and of the HPA axis is observed. [ 20,22,40,41,46 ] The smoothing of the circadian rhythm of the SCN in the elderly correlates with neuronal degeneration in SCN and is often associated with earlier falling asleep and waking up. [ 20,26,41 ] The smoothing with aging of the circadian rhythm of HPA axis activity may be accompanied by an increase in the secretion of CORT in the evening and at night in humans and primates [ 20–22,25,35,40,47 ] and in rodents in the daytime.…”

Withania somnifera and Centella asiatica Extracts Ameliorate Behavioral Deficits in an In Vivo Drosophila melanogaster Model of Oxidative Stress

“…Sleep patterns in male and female CS and sniffer flies aged 1 week were assessed using the Drosophila Activity Monitoring Systems (DAMS) as described by Cassar et al [ 40 ] and Metaxakis et al [ 41 ]. For 7 days prior to placement in the monitors, CS flies were fed standard Drosophila food while sniffer flies were fed either standard Drosophila food or standard food supplemented with WS (0.5 mg/g or 2 mg/g).…”

FTD-associated mutations in Tau result in a combination of dominant and recessive phenotypes

“…The knock-in lines were created by replacing the dTau coding region with the cDNA for the human Tau 1N4R isoform using the CRISPR/Cas9 genomic editing system. A more detailed description is given in ( Cassar et al, 2020 ). These flies were originally in the w 1118 background but were backcrossed to CS to prevent phenotypes due to the w mutation.…”