Long-term locus coeruleus stimulation exacerbates tau pathology in PS19 mice

BackgroundAlzheimer'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 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.ObjectiveTo evaluate the impact of long-term LC stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice using behavioral paradigms, electrophysiological recordings, and immunofluorescence analysis.MethodsThe 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 (LTP) was recorded to evaluate the effect of long-term LC stimulation on synaptic plasticity. Immunofluorescence was employed to examine tau phosphorylation, neurodegeneration, and neuroinflammation.ResultsLong-term LC stimulation in PS19 mice exacerbated spatial memory deficits in the water maze, impaired contextual fear memory, reduced hippocampal LTP, and increased asparagine endopeptidase (AEP) expression, tau hyperphosphorylation, and neuroinflammation.ConclusionsLong-term LC stimulation may exacerbate memory deficits in PS19 mice by impairing synaptic plasticity and increasing neural degeneration in the hippocampus. Increased AEP expression and tau hyperphosphorylation in the LC further suggest a possible association between LC overactivation and AEP-associated tau pathology.