title: GRK5 dysfunction accelerates tau hyperphosphorylation in APP (swe) mice through impaired cholinergic activity.
abstract: Recent studies have suggested that G-protein-coupled receptor kinase 5 (GRK5) deficiency plays a significant role in the pathogenesis of early Alzheimer's disease. Mild soluble β-amyloid accumulation can result in reduced membrane (functional) and elevated cytosolic levels of GRK5. Dysfunction of GRK5 impairs the desensitization of presynaptic muscarinic 2 (M2) autoreceptors, which results in presynaptic M2 hyperactivity and inhibits acetylcholine (ACh) release. GRK dysfunction also promotes a deleterious cycle that further increases β-amyloid accumulation and exaggerates tau hyperphosphorylation in the hippocampus. However, the pathogenic effect of GRK5 dysfunction through targeting tau hyperphosphorylation remains unclear. Here we examined not only the reduced membrane (functional) and elevated cytosolic levels of GRK5 but also the increased levels of hyperphosphorylated tau in the hippocampi of aged APP(swe) mice (11 months of age). Moreover, western blotting analyses revealed the changes in the location of activity of both protein kinase C (PKC) and glycogen synthase kinase3β (GSK3β) in the hippocampus of aged APP(swe) mice in which GRK5 translocation occurred. Moreover, treatment with methoctramine, a selective M2 antagonist, partially corrected the difference between wild-type control mice and GRK5-dysfunctional APP (swe) mice in hippocampal ACh release, PKC and GSK3β activities, as well as tau hyperphosphorylation. In contrast, the GSK3β inhibitor lithium chloride significantly reduced tau hyperphosphorylation in GRK5-defective APP (swe) mice, but failed to enhance PKC activity and ACh release in the hippocampi of GRK5-defective APP (swe) mice. Taken together, these findings indicate that GRK5 dysfunction accelerated tau hyperphosphorylation in APP(swe) mice by activating GSK3β through impaired cholinergic activity.
authors.affiliation: Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Liyun
authors.initials: L
authors.lastname: Chen
authors.forename: Guangli
authors.initials: G
authors.lastname: Shen
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Lijuan
authors.initials: L
authors.lastname: Shangguan
authors.forename: Maolin
authors.initials: M
authors.lastname: He
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000375:Aging; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D003959:Diamines / Q000627:therapeutic use; D004195:Disease Models, Animal; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010276:Parasympatholytics / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D003959:Diamines; D010276:Parasympatholytics; D016875:tau Proteins; D054774:G-Protein-Coupled Receptor Kinase 5; C517897:Grk5 protein, rat; D018021:Lithium Chloride; D000109:Acetylcholine; C054938:methoctramine