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 -amyloid precursor protein (APP) carrying Swedish mutations (Tg2576 or APPsw) resulted in significantly increased -amyloid (A) accumulation, including increased A ؉ plaque burdens and soluble A in brain lysates and interstitial fluid (ISF). In addition, secreted -APP fragment (sAPP) also increased, whereas fulllength APP level did not change, suggesting an alteration in favor of -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. In contrast, a cholinesterase inhibitor, eserine, although significantly decreasing the ISF A 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 further in both animals. Altogether, these findings indicate that GRK5 deficiency accelerates -amyloidogenic APP processing and A 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.Alzheimer disease (AD 3 ) is a devastating neurodegenerative disorder clinically characterized by progressive loss of memory and other neurological functions. Given that basal forebrain cholinergic neurons are the fundamental basis for memory function, any of the pathological causes in AD, no matter whether they are the hallmark changes of -amyloid (A)-enriched senile plaques and neurofibrillary tangles or of the prominent inflammation, have to eventually converge to the extensive basal forebrain cholinergic neuronal loss in AD.Mounting evidence suggests that the excessive accumulation of A is a paramount pathological event leading to AD, either by direct neuronal toxicity or by indirect exacerbation of inflammatory damage to neurons (1, 2). The amyloid precursor protein (APP) can be proteolytically processed either through the -amyloidogenic pathway by -and ␥-secretases or via the non--amyloidogenic pathway by ␣-secretase. The regulation of these two mutually exclusive pathways determines the amount of A production and is thus critically important for the pathogenesis of AD. Previous studies have demonstrated that proteolytic APP processing can be regulated by a variety of G protein-coupled receptors, including cholinergic, se...
Why certain diseases primarily affect one specific neuronal subtype rather than another is a puzzle whose solution underlies the development of specific therapies. Selective basal forebrain cholinergic (BFC) neurodegeneration participates in cognitive impairment in Alzheimer’s disease (AD), yet the underlying mechanism remains elusive. Here, we report the first recapitulation of the selective BFC neuronal loss that is typical of human AD in a mouse model termed GAP. We created GAP mice by crossing Tg2576 mice that over-express the Swedish mutant human β-amyloid precursor protein gene with G protein-coupled receptor kinase-5 (GRK5) knockout mice. This doubly defective mouse displayed significant BFC neuronal loss at 18 months of age, which was not observed in either of the singly defective parent strains or in the wild type. Along with other supporting evidence, we propose that GRK5 deficiency selectively renders BFC neurons more vulnerable to degeneration.
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