Abstract
Our work explores the relationship between G protein-coupled receptor kinase-5 (GRK5) single nucleotide polymorphisms and Alzheimer's disease risk. We confirmed that GRK5 translocates from the cellular membrane to the cytosol in the hippocampus of Alzheimer's disease mice and that GRK5 deficiency promotes tau hyperphosphorylation, a hallmark of Alzheimer's disease pathology. Our results indicate that one functional variant, or mutant, of GRK5 (GRK5-Gln41Leu) decreased GRK5 translocation from the membrane to the cytoplasm and reduced tau hyperphosphorylation, whereas, another GRK5 mutant (GRK5-Arg304His) increased GRK5 translocation to the cytoplasm and promoted tau hyperphosphorylation. In addition, case-control studies revealed that GRK5-Gln41Leu is associated with a lower risk of late-onset Alzheimer's disease. Our findings suggest that the GRK5-Gln41Leu mutant may resist tau hyperphosphorylation by promoting GRK5 membrane stability and, in effect, may contribute to lower Alzheimer's disease risk.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder clinically characterized by the progressive loss of memory and other neurological functions
We first examined the hippocampi of APP/PS1 transgenic mice of different ages to determine whether the subcellular distribution of G protein-coupled receptor kinase-5 (GRK5) was altered
Recent studies suggest that GRK5 deficiency may impair the desensitization of presynaptic muscarinic 2 (M2) autoreceptors [5, 20]
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder clinically characterized by the progressive loss of memory and other neurological functions. Amyloid precursor (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), play extremely important roles in Aβ42 metabolism, and these mutations have been identified as risk factors for Early Onset Alzheimer Disease (EOAD) [1, 2]. GRK5 dysfunction mediates the deleterious cycle between cholinergic hypofunction and tau hyperphosphorylation, leading to increased β-amyloid deposition in the hippocampus [8, 9]. It has been reported that the proteolytic processing of APP is regulated by a variety of GPCRs, including cholinergic, serotoninergic, and glutamatergic receptors [9], suggesting that GRK5 may play a role in GPCRs mediated APP metabolic pathway
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