GRK5 deficiency leads to early Alzheimer-like pathology and working memory impairment

GRK5 Deficiency Leads to Reduced Hippocampal Acetylcholine Level via Impaired Presynaptic M2/M4 Autoreceptor Desensitization

“…Here we show a clear presynaptic cholinergic hypofunction in the absence of degenerative changes. We have previously observed that the aged GRK5KO mice displayed mild cholinergic and synaptic degenerative changes (5). In this study, we showed that the hippocampal cholinergic hypofunction can occur without obvious structural degenerative changes, and this hippocampal cholinergic hypofunction without structural degeneration in young mice precedes hypofunction with structural degeneration in aged GRK5KO mice.…”

“…Aged GRK5KO mice displayed mild cholinergic and synaptic degenerative changes (5). Therefore, without correction of their structural abnormalities, it is impropriate to directly compare the cholinergic functional difference between aged WT and GRK5KO mice.…”

“…For the mice, at euthanasia, cold phosphate-buffered saline-perfused brains were dissected to obtain hippocampus. Except for the cellular fraction preparation, which is described above, all other protein extract preparation, total protein content determination, Western blotting, and semi-quantitative analyses were performed as previously described (5,19,25). The only exception was the dilution rates for the different primary antibodies, which include synaptophysin (Sigma; 1:400), synapsin-IIa (BD Biosciences, San Jose, CA; 1:5,000), synaptotagmin (BD Biosciences; 1:1,000), SNAP-25 (BD Biosciences; 1:1,000), neuronal growth associated protein-43 (GAP-43; Sigma; 1:500), M1 and M4 (Santa Cruz Biotechnology, Santa Cruz, CA; 1:200), M2 (Santa Cruz Biotechnology; 1:100), acetylcholine esterase (Santa Cruz Biotechnology; 1:500), choline acetyltransferase (ChAT; Chemicon, Temecula, CA; 1:800), HACT (Chemicon; 1:4,000), vesicular acetylcholine transporter (VAChT; Santa Cruz Biotechnology; 1:200), hrGFP (Stratagene, La Jolla, CA; 1:5,000), and ␤-actin (Sigma; 1:2,500).…”

“…Moreover, the aged GRK5 knock-out (GRK5KO) mouse, which models this GRK5 deficiency in the absence of exogenous mutant human ␤-amyloid precursor protein (␤-APP) or any other known AD-related genes (i.e. presenilins or tau), develops axonal defects and mild cholinergic degeneration with associated amnestic mild cognitive impairment (5). When Swedish mutant ␤APP is overexpressed in the GRK5KO mice by cross-breeding with Swedish APP transgenic mice, the aged double mutant mice display significantly exaggerated brain inflammation (6).…”

Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases

“…Moreover, a Q41L polymorphism within the regulator of G protein signaling homology (RH) domain in GRK5 is prevalent in African Americans and has an enhanced ability to desensitize the ␤ 2 -adrenergic receptor (␤ 2 AR) (12) and protect against the development of congestive heart failure (13). GRK5 has also been linked with type 2 diabetes (14), prostate tumor growth (15) and metastasis (16), Parkinson disease with dementia (17), synuclein phosphorylation and aggregation in sporadic Parkinson disease (18), and Alzheimer pathology in mice and humans (19), possibly due to its role in neurite outgrowth, learning, and memory (20). Taken together, these studies reveal that GRK5 is implicated in many different human diseases and may provide an important therapeutic target in the treatment of cardiovascular disease, neurological and metabolic disorders, and cancer.…”