Summary

Patients with Alzheimer’s disease (AD) exhibit sleep disturbances, specifically deficits in deep non-rapid eye movement (NREM) sleep. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Also, it is not clear if these sleep disturbances are a cause or effect of AD. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP mice. We monitored astrocytic calcium transients expressing genetically encoded calcium reporter Yellow Cameleon 3.6 (YC3.6) using multiphoton microscopy. The power but not the frequency of astrocytic calcium transients associated with slow waves was reduced. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.

Keywords: Optogenetics, astrocytes, sleep, slow oscillations, Alzheimer’s disease, multiphoton imaging, neuroinflammation, memory consolidation, calcium

This work was supported by the BrightFocus Foundation Grant A2020833S; the Alzheimer’s Association Grant AARG-18-52336; National Institutes of Health Grant R01AG066171.