Illuminating early Alzheimer's disease: optogenetic approaches to restoring sleep-dependent slow oscillation

Abstract Alzheimer’s disease is a leading cause of dementia. In addition to progressive cognitive decline, Alzheimer’s patients experience sleep impairments, specifically deficits in the quantity and quality of deep non-rapid eye movement (NREM) sleep. Impairments in slow sleep-dependent brain rhythms, slow oscillation or slow waves, have been reported in the early prodromal stages of the disease and could serve as early Alzheimer’s disease biomarkers. Slow waves play an important role in memory consolidation during NREM sleep. Thus, the dementia observed in Alzheimer’s patients could be attributed, at least partially, to slow wave impairments. Restoring slow oscillation may alleviate cognitive symptoms and slow disease progression. However, the mechanisms underlying slow wave impairments in Alzheimer’s disease remained elusive. It was unclear whether slow wave impairments were simply symptomatic of the disease or actively contributed to Alzheimer’s disease progression. In this review, we discuss how the application of optogenetics to cortical circuits in mouse models of amyloidosis has enabled dissection of circuit impairments underlying disrupted slow wave activity. We argue that slow wave impairments actively contribute to Alzheimer’s disease. Optogenetic restoration of slow waves slowed disease progression, whereas exacerbating slow wave impairments facilitated Alzheimer’s disease. We highlight recent advances in targeting cortical excitatory pyramidal neurons, GABAergic interneurons, and astrocytes, which regulate slow wave dynamics. Optogenetic stimulation of these cell types at physiological frequency restored slow oscillation power, reduced amyloid pathology, normalized neuronal calcium levels, and rescued memory as well as sleep in Alzheimer’s disease mouse models. Collectively, these findings support a causal link between impaired slow oscillation and Alzheimer’s disease progression, and position slow-wave restoration as a promising therapeutic strategy for Alzheimer’s disease.