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GRK5 deficiency accelerates {beta}-amyloid accumulation in Tg2576 mice via impaired cholinergic activity
Shaowu Cheng1, Longxuan Li, Shuangteng He
1Laboratory for Alzheimer's Disease and Aging Research, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri 64128, USA.
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.
Insights
G protein-coupled receptor kinase 5 (GRK5) deficiency worsens Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- G protein-coupled receptor kinase 5 (GRK5) deficiency is linked to Alzheimer disease pathogenesis.
- GRK5 deficiency impairs M2 autoreceptor desensitization, leading to hyperactivity and reduced acetylcholine release.
- The precise role of GRK5 in Alzheimer disease (AD) requires further elucidation.
Purpose of the Study:
- To investigate the impact of GRK5 deficiency on amyloid precursor protein (APP) processing and amyloid-beta (Aβ) accumulation in a mouse model of Alzheimer disease.
- To explore the therapeutic potential of targeting M2 autoreceptors and cholinergic activity in mitigating AD pathology associated with GRK5 deficiency.
Main Methods:
- Utilized transgenic mice (APPsw) with GRK5 gene inactivation to study Aβ accumulation and APP processing.
- Administered methoctramine (M2 antagonist) and eserine (cholinesterase inhibitor) to assess their effects on ISF Aβ levels.
- Analyzed Aβ plaque burdens, soluble Aβ, and full-length APP levels in brain lysates and interstitial fluid (ISF).
Main Results:
- GRK5 deficiency in APPsw mice significantly increased Aβ accumulation, including plaque burden and soluble Aβ in brain and ISF.
- APP processing shifted towards the amyloidogenic pathway, with increased secreted β-APP fragment (sAPPβ) and unchanged full-length APP.
- Methoctramine administration normalized ISF Aβ levels between control and GRK5-deficient APPsw mice.
- Eserine reduced ISF Aβ but did not correct the difference between groups; combined therapy showed additive effects.
Conclusions:
- GRK5 deficiency accelerates amyloidogenic APP processing and Aβ accumulation in APPsw mice, mediated by impaired cholinergic activity.
- Presynaptic M2 hyperactivity is a key target for ameliorating the pathological effects of GRK5 deficiency in AD.
- Combination therapy with an M2 antagonist and a cholinesterase inhibitor may offer maximal benefits for both amyloid pathology and cholinergic dysfunction in Alzheimer disease.
