Sleep, neuronal hyperexcitability, inflammation and neurodegeneration: Does early chronic short sleep trigger and is it the key to overcoming Alzheimer's disease?

Abstract

Evidence links neuroinflammation to Alzheimer's disease (AD); however, its exact contribution to the onset and progression of the disease is poorly understood. Symptoms of AD can be seen as the tip of an iceberg, consisting of a neuropathological build-up in the brain of extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated aggregates of Tau (pTau), which are thought to stem from an imbalance between its production and clearance resulting in loss of synaptic health and dysfunctional cortical connectivity. The glymphatic drainage system, which is particularly active during sleep, plays a key role in the clearance of proteinopathies. Poor sleep can cause hyperexcitability and promote Aβ and tau pathology leading to systemic inflammation. The early neuronal hyperexcitability of γ-aminobutyric acid (GABA)-ergic inhibitory interneurons and impaired inhibitory control of cortical pyramidal neurons lie at the crossroads of excitatory/inhibitory imbalance and inflammation. We outline, with a prospective framework, a possible vicious spiral linking early chronic short sleep, neuronal hyperexcitability, inflammation and neurodegeneration. Understanding the early predictors of AD, through an integrative approach, may hold promise for reducing attrition in the late stages of neuroprotective drug development.

Keywords: Alzheimer’s disease; Disease modification therapy; Dysfunctional clearance; Early chronic short sleep; Early translational diagnosis; Inflammation; Neuronal hyperexcitability.