Tau hyperphosphorylation in Locus Coeruleus mediates early-onset sleep disruption in mouse model of AD amyloidosis by causing neuronal hyperexcitability
Sleep disturbances are common in patients with neurodegeneration, including Alzheimer's disease (AD), which can occur at early stages of AD and are proposed as potent risk factors for disease onset and progression. The underlying causes of this early-onset sleep disturbances remain unclear. Here we found that 5xFAD transgenic mice display significantly reduced sleep and prolonged wakefulness as early as 2 months of age. This early-onset sleep disruption correlates with increased tonic neuronal activity in the Locus Coeruleus (LC), which is mediated by heightened neuronal excitability due to impaired Kv4 and Kv7 channel conductance. Notably, we discovered that these young transgenic mice develop brain region-specific tau hyperphosphorylation (p-tau) in the LC. To investigate the pathological role of LC p-tau, we induce p-tau by inoculating synthetic human tau fibril into the LC of wild-type mice. This fibril inoculation replicated the reduction in Kv conductance and increased LC neuronal excitability in a tau-dependent manner. Modulating Kv4 and Kv7 channels restored normal excitability in both fibril-inoculated wild-type mice and young 5xFAD mice. Furthermore, fibril inoculation was sufficient to induce 5xFAD-like sleep disruptions in wild-type mice. Finally, pharmacological reduction of p-tau, both ex vivo and in vivo, effectively restored normal electrophysiological properties of LC neurons and normalized sleep/wake patterns in fibril-inoculated wild-type mice and young 5xFAD mice. Therefore, our findings identify a neural mechanism underlying early-onset sleep disturbances in a mouse model of AD amyloidosis and highlight the pathological consequences of LC tau hyperphosphorylation. Overall design: Mice were anesthetized with isoflurane vapor and rapidly sacrificed. Brain slices containing LC region were collected by a vibratome (1200S, Leica) in ice-cold dissection buffer. LC regions were micro-dissected on ice with sterile disposable biopsy punch (#33-31, Integra Lifesciences) then quickly frozen with liquid nitrogen and stored at -80°C until used. TRIzol® Reagent (Invitrogen Life Technologies) was used to retrieve total RNA. RNA concentration and quality were determined by NanoDrop spectrophotometer (Thermo Scientific). Only high-quality RNA samples (OD260 / 280 = 1.8 ~ 2.2, OD260 / 230 = 1.9, RIN = 9.0) were used for the library and bulk RNA sequencing (Shanghai Personal Biotechnology Cp. Ltd.).