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

Area of Science:

• Neuroscience
• Neurology
• Pathology

Background:

• Alzheimer's disease (AD) involves amyloid-β plaques and tau tangles, with early degeneration in the locus coeruleus (LC).
• Previous research shows mixed effects of LC modulation on memory in AD models.
• The impact of long-term LC stimulation on memory, synaptic plasticity, and tauopathy in tauopathy models is not well understood.

Purpose of the Study:

• To investigate the effects of long-term LC stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice.
• To assess behavioral, electrophysiological, and molecular changes associated with sustained LC activation in an AD mouse model.

Main Methods:

• PS19 mice underwent long-term LC stimulation.
• Memory was assessed using the radial arm water maze and fear conditioning tests.
• Synaptic plasticity was evaluated via hippocampal long-term potentiation (LTP) recordings.
• Tau phosphorylation, neurodegeneration, and neuroinflammation were analyzed using immunofluorescence.

Main Results:

• Long-term LC stimulation exacerbated spatial memory deficits and impaired contextual fear memory in PS19 mice.
• Hippocampal LTP was reduced, indicating impaired synaptic plasticity.
• Increased asparagine endopeptidase (AEP) expression, tau hyperphosphorylation, and neuroinflammation were observed.

Conclusions:

• Long-term LC stimulation may worsen memory deficits in PS19 mice by impairing synaptic plasticity and increasing hippocampal neural degeneration.
• Elevated AEP expression and tau hyperphosphorylation in the LC suggest a link between LC overactivation and AEP-mediated tau pathology in AD.