Tau-driven hyperexcitability of locus coeruleus noradrenergic neurons underlies sleep fragmentation and cognitive decline in mice

05/11/2026

AI Summary

Pathological tau selectively increases intrinsic excitability of locus coeruleus dopamine-β-hydroxylase noradrenergic neurons
Tau-induced hyperactivity of LCDBH neurons disrupts sleep homeostasis, reducing NREM and slow-wave activity, increasing fragmentation and microarousals, delaying sleep onset
Optogenetic suppression of LCDBH tau activity restores sleep architecture and rescues recognition memory, identifying LCDBH hyperexcitability as a therapeutic target in preclinical AD

TL;DR (AI Generated)

Using P301S transgenic mice and cell-type-specific tau overexpression models, we show that pathological tau accumulation selectively increases the intrinsic excitability of LCDBH neurons.

Tau-induced neuronal hyperactivity disrupts sleep homeostasis, reduces non-rapid eye movement (NREM) sleep and slow-wave activity, increases sleep fragmentation and microarousals, and delays both anesthetic induction and sleep onset.

Our findings demonstrate that tau-driven hyperexcitability of LCDBH neurons is a core driver of early sleep and cognitive impairments in AD, providing a mechanistic insight and potential target for preclinical AD treatment.

Basic summary

Cell Rep. 2026 Nov 3;45(11):118273. doi: 10.1016/j.celrep.2026.118273. Online ahead of print.

ABSTRACT

Early sleep disruption is a hallmark of preclinical Alzheimer’s disease (AD), but its underlying mechanisms are unclear. The locus coeruleus (LC) dopamine-β-hydroxylase noradrenergic (LC^DBH) neurons are vulnerable to early tau pathology in AD. Using P301S transgenic mice and cell-type-specific tau overexpression models, we show that pathological tau accumulation selectively increases the intrinsic excitability of LC^DBH neurons. Tau-induced neuronal hyperactivity disrupts sleep homeostasis, reduces non-rapid eye movement (NREM) sleep and slow-wave activity, increases sleep fragmentation and microarousals, and delays both anesthetic induction and sleep onset. Furthermore, tau overexpression in LC^DBH neurons leads to significant recognition memory deficits. Notably, optogenetic suppression of LC^DBH-tau neuronal activity reverses sleep disturbances and rescues cognitive dysfunction. Our findings demonstrate that tau-driven hyperexcitability of LC^DBH neurons is a core driver of early sleep and cognitive impairments in AD, providing a mechanistic insight and potential target for preclinical AD treatment.

PMID:42981191 | DOI:10.1016/j.celrep.2026.118273

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