Acute Effects of Muscarinic M1 Receptor Modulation on A beta PP Metabolism and Amyloid-beta Levels in vivo: A Microdialysis Study

作者：Welt Tobias^*; Kulic Luka; Hoey Sarah E; McAfoose Jordan; Spaeni Claudia; Chadha Antonella Santuccione; Fisher Abraham; Nitsch Roger M

来源：Journal of Alzheimer's Disease, 2015, 46(4): 971-982.

DOI：10.3233/JAD-150152

• A beta PP processing
• A beta PP transgenic mice
• Alzheimer's disease
• amyloid-beta
• microdialysis
• muscarinic acetylcholine receptor

Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-beta (A beta) production by shifting endoproteolytic amyloid-beta protein precursor (A beta PP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit A beta production in awake and freely moving A beta PP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal A beta concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) A beta levels while treatment with the M1 antagonist dicyclomine increased ISF A beta levels reaching significance within 120 minutes of treatment. The reduction in A beta levels was associated with PKC alpha and ERK activation resulting in increased levels of the alpha-secretase ADAM17 and a shift in A beta PP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKC alpha, and led to an elevation of beta-secretase levels associated with increased amyloidogenic A beta PP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of A beta and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on A beta PP/A beta metabolism.

• 出版日期2015