Fig. 4

Neuronal control of the sleep–wake cycle and therapeutic targets for sleep restoration in Alzheimer’s disease. The sleep–wake cycle is controlled by neuronal populations vulnerable in Alzheimer’s disease (AD). Circadian rhythmicity is mediated by hypothalamic neuronal activity and melatonin release from the pineal gland, normally maintaining a healthy sleep–wake cycle. Sleep is promoted by activity of melanin-concentrating hormone (MCH)-neurons in the hypothalamus and broad (including cortical, hippocampal, hypothalamic) GABAergic inhibitory signals. In the sleep-state, protein clearance and memory consolidation, mediated by entorhinal-hippocampal circuitry, are enhanced. Conversely, wakefulness and arousal are promoted by activity of histaminergic and orexinergic neurons of the hypothalamus, and noradrenergic neurons in the locus coeruleus. In the wake-state, cognitive and memory processes (mediated by entorhinal-hippocampal circuitry) occur with higher rates of neuronal activity, which potentiates Aβ and tau spread. Therapeutics to enhance sleep in AD present a unique opportunity to simultaneously improve the behavioral phenotype and reduce proteinopathy by improved proteostatic clearance. Enhancement of GABA signalling with pharmacological and non-pharmacological interventions may broadly improve network dysfunction in AD, for memory and sleep circuits. Notably, gamma entrainment is a novel and non-invasive strategy. Sleep promotion and balancing of circadian arrhythmicity can be accomplished via supplementation of the biologically active hormone melatonin, or non-pharmacological lifestyle interventions, including behavioral, light, music, and other auditory therapies. Pharmacological antihistamines and orexin antagonists decrease wake/arousal-signals and promote sleep. Potential exists for targeting of additional neuronal pathways to promote sleep, including noradrenergic signaling which is affected early in AD; the α2 adrenergic receptor agonist dexmedetomidine has been tested (see Table 2), but is more suitable as a sedative than therapeutic. Furthermore, the antidepressant trazodone has potential for improving sleep in AD acting through neuromodulation of serotonergic, adrenergic, histaminergic, and cholinergic pathways, as well as modifying the UPR. Future work is necessary to characterize and discover new sleep- and proteostasis-targeted therapies in AD. See Tables 2 and 3 for sleep-related AD clinical trials and their relevance to proteostasis. Created with BioRender.com