Long-term Locus Coeruleus Stimulation Exacerbates Tau Pathology in PS19 Mice.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau tangles. The locus coeruleus (LC) is among the first brain regions to show degeneration and Tau pathology during the early stages of AD. Previous studies have demonstrated that short-term chemogenetic LC stimulation can improve memory performance in the TgF344-AD rat model, while long-term norepinephrine (NE) reuptake inhibition can worsen memory deficits in the ADLP(Tau) mouse model. However, the effects of long-term LC stimulation in Tau mouse models on memory, synaptic plasticity, and tauopathy remain unclear. OBJECTIVE: To evaluate the impact of long-term locus coeruleus stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice using behavioral paradigms, electrophysiological recordings, and immunohistochemical analysis. METHODS: The radial arm water maze and fear conditioning test were conducted to assess memory performance in PS19 mice with and without long-term LC stimulation. Hippocampal long-term potentiation was recorded to evaluate the effect of long-term LC stimulation on synaptic plasticity. Immunohistochemistry was employed to examine Tau phosphorylation, neurodegeneration, and neuroinflammation. RESULTS: Long-term LC stimulation in PS19 mice exacerbated spatial memory deficits in the water maze, impaired contextual fear memory, reduced hippocampal LTP, and increased AEP expression, Tau hyperphosphorylation, and astrocyte activation. CONCLUSION: Long-term LC stimulation may exacerbate memory deficits in PS19 mice by impairing synaptic plasticity and increasing neural degeneration in the hippocampus. Elevated norepinephrine levels resulting from long-term LC stimulation may increase AEP expression, contributing to Tau hyperphosphorylation in the LC.