Title : Brain region-specific tau hyperphosphorylation mediates sleep disruption associated with early stage of Alzheimer's diseases
Abstract:
Sleep disorders are commonly found in Alzheimer's disease (AD) patients, which can occur at very early stage of AD and are proposed as potent risk factors for disease onset and progression. What may cause these early-onset sleep deficits remains unexplored. Here by thoroughly characterizing the sleep/wake pattern of 2-month-old 5xFAD mice, we first confirmed that these AD transgenic mice show abnormal sleep at young age similar to human patients. Specifically, they show shortened sleep and prolonged wake duration. Interestingly, we found that these AD mice develop brain region-specific tau hyperphosphorylation (p-tau) in Locus Coeruleus (LC). Importantly, selective elevation of p-tau in LC neurons is sufficient to trigger AD-like sleep phenotype in wildtype mice, supporting a critical causal role of LC p-tau in AD-associated early sleep disruption. We at last revealed that p-tau alters LC neural excitability and pharmacologically reducing p-tau rescues LC neuron hyperexcitability both in wildtype and young 5xFAD mice. Therefore, our study unveil a novel pathomechanism associated with early stage of AD.
