GRK5 Deficiency Accelerates β-Amyloid Accumulation in Tg2576 Mice via Impaired Cholinergic Activity

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 beta-amyloid precursor protein (APP) carrying Swedish mutations (Tg2576 or APPsw) resulted in significantly increased beta-amyloid (A beta) accumulation, including increased A beta(+) plaque burdens and soluble A beta in brain lysates and interstitial fluid (ISF). In addition, secreted beta-APP fragment (sAPP beta) also increased, whereas full-length APP level did not change, suggesting an alteration in favor of beta-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 A beta. In contrast, a cholinesterase inhibitor, eserine, although significantly decreasing the ISF A beta in both control and GRK5-deficient APPsw mice, failed to correct the difference between them. However, combining eserine with methoctramine additively reduced the ISF A beta further in both animals. Altogether, these findings indicate that GRK5 deficiency accelerates beta-amyloidogenic APP processing and A beta 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.