Unraveling the link between circadian rhythm-neural activity and Alzheimer’s disease with human cortical organoid models

Alzheimer’s disease (AD) is the most common form of dementia among the elderly. Disruption of the circadian rhythm (CR) can occur early during AD progression and further, may control neural activity patterns, amyloid beta (A) and Tau-phosphorylation levels in the brain. However, the mechanisms underlying the link between CR, neural activity patterns and AD in specific brain cell types are still unknown.
This project investigates how cellular CR contributes to AD pathogenesis using human cortical organoids (hCOs) derived from induced pluripotent stem cells (hiPSCs). We demonstrate the presence of CR in in vitro hCOs, attested by the oscillatory expression of CR modulators. Further, pharmacological activation of cholinergic and noradrenergic receptors led to increased c-Fos expression and calcium dynamics in hCOs following 6 hours agonist exposure, with basal levels recovered 5-day post-exposure, suggesting an increase in neural activity in hCOs. Interestingly, this treatment increased the clearance rate of soluble A from hCOs medium, suggesting that neural activity may promote A degrading mechanisms in the cell. Next, to assess alterations in neural rhythms and molecular pathways in AD brain cells, we generated hCOs from familial AD (FAD) patient cells. FAD hCOs showed increased c-Fos+ cells located around Aβ aggregates, suggesting local hyperactivity. Interestingly, most c-Fos+ cells had an astrocyte identity, highlighting a potential early role for astrocytes in AD.
These observations suggest that CR-neural activity alterations may be an early mechanism in AD pathogenesis, highlighting that modulation of CR-neural activity patterns may be a promising target for preventive and therapeutic AD strategies. Further, hCO models could be a useful tool to study the link between CR-neural activity and AD.