GRK5 dysfunction accelerates tau hyperphosphorylation in APP (swe) mice through impaired cholinergic activity.

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• G-protein-coupled receptor kinase 5 (GRK5) deficiency is implicated in early Alzheimer's disease pathogenesis.
• GRK5 dysfunction leads to reduced membrane levels, impaired muscarinic 2 (M2) autoreceptor desensitization, and inhibited acetylcholine (ACh) release.
• This dysfunction contributes to increased beta-amyloid and tau hyperphosphorylation.

Purpose of the Study:

• To investigate the role of GRK5 dysfunction in tau hyperphosphorylation.
• To examine the impact of GRK5 dysfunction on protein kinase C (PKC) and glycogen synthase kinase3β (GSK3β) activity.
• To evaluate the therapeutic potential of M2 antagonism and GSK3β inhibition in a mouse model.

Main Methods:

• Analysis of GRK5, hyperphosphorylated tau, PKC, and GSK3β levels and activity in hippocampi of aged APP(swe) mice.
• Assessment of hippocampal ACh release in GRK5-dysfunctional mice.
• Treatment with methoctramine (M2 antagonist) and lithium chloride (GSK3β inhibitor) to assess their effects.

Main Results:

• Aged APP(swe) mice exhibited reduced membrane GRK5, elevated cytosolic GRK5, and increased hyperphosphorylated tau.
• GRK5 dysfunction correlated with altered PKC and GSK3β activity and impaired ACh release.
• Methoctramine partially ameliorated ACh release, enzyme activities, and tau hyperphosphorylation; lithium chloride reduced tau hyperphosphorylation but not PKC activity or ACh release.

Conclusions:

• GRK5 dysfunction accelerates tau hyperphosphorylation in APP(swe) mice via GSK3β activation, linked to impaired cholinergic activity.
• Targeting M2 autoreceptors may offer a therapeutic strategy for Alzheimer's disease.
• GRK5 plays a critical role in regulating cholinergic function and tau pathology.