ArticleThe Journal of biological chemistry2010
GRK5 deficiency accelerates {beta}-amyloid accumulation in Tg2576 mice via impaired cholinergic activity.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 37 citations in OpenAlex.
- Rare and novel genetic variants in sporadic and familial Alzheimer's disease: insights from the first Saudi cohort.Frontiers in aging · 2026Article
- Understanding How Physical Exercise Improves Alzheimer's Disease: Cholinergic and Monoaminergic Systems.Frontiers in aging neuroscience · 2022Review
- GRK5 Deficiency Causes Mild Cognitive Impairment due to Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2022Review
- G protein-coupled receptor kinases are associated with Alzheimer's disease pathology.Neuropathology and applied neurobiology · 2021Article
- Targeting GRK5 for Treating Chronic Degenerative Diseases.International journal of molecular sciences · 2021Review
- Review
- Beta-Amyloid-Dependent miRNAs as Circulating Biomarkers in Alzheimer's Disease: a Preliminary Report.Journal of molecular neuroscience : MN · 2020Article
- Nanocurcumin: A Promising Candidate for Therapeutic Applications.Frontiers in pharmacology · 2020Review
- GRK5 - A Functional Bridge Between Cardiovascular and Neurodegenerative Disorders.Frontiers in pharmacology · 2018Review
- The influence of two functional genetic variants of GRK5 on tau phosphorylation and their association with Alzheimer's disease risk.Oncotarget · 2017Article
- GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability.Scientific reports · 2016Article
- Differentiation renders susceptibility to excitotoxicity in HT22 neurons.Neural regeneration research · 2013Article
- G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms.High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension · 2013Review
- G-protein-coupled receptor kinase-5 mediates inflammation but does not regulate cellular infiltration or bacterial load in a polymicrobial sepsis model in mice.Journal of innate immunity · 2013Article
- G protein-coupled receptor kinases: more than just kinases and not only for GPCRs.Pharmacology & therapeutics · 2012Review
- Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis.Journal of cellular and molecular medicine · 2011Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Membrane G protein-coupled receptor kinase 5 (GRK5) deficiency is linked to Alzheimer disease, yet its precise roles in the disease pathogenesis remain to be delineated. We have previously demonstrated that GRK5 deficiency selectively impairs desensitization of presynaptic M2 autoreceptors, which causes presynaptic M2 hyperactivity and inhibits acetylcholine release. Here we report that inactivation of one copy of Grk5 gene in transgenic mice overexpressing β-amyloid precursor protein (APP) carrying Swedish mutations (Tg2576 or APPsw) resulted in significantly increased β-amyloid (Aβ) accumulation, including increased Aβ(+) plaque burdens and soluble Aβ in brain lysates and interstitial fluid (ISF). In addition, secreted β-APP fragment (sAPPβ) also increased, whereas full-length APP level did not change, suggesting an alteration in favor of β-amyloidogenic APP processing in these animals. Reversely, perfusion of methoctramine, a selective M2 antagonist, fully corrected the difference between the control and GRK5-deficient APPsw mice for ISF Aβ. In contrast, a cholinesterase inhibitor, eserine, although significantly decreasing the ISF Aβ in both control and GRK5-deficient APPsw mice, failed to correct the difference between them. However, combining eserine with methoctramine additively reduced the ISF Aβ further in both animals. Altogether, these findings indicate that GRK5 deficiency accelerates β-amyloidogenic APP processing and Aβ accumulation in APPsw mice via impaired cholinergic activity and that presynaptic M2 hyperactivity is the specific target for eliminating the pathologic impact of GRK5 deficiency. Moreover, a combination of an M2 antagonist and a cholinesterase inhibitor may reach the maximal disease-modifying effect for both amyloid pathology and cholinergic dysfunction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.