Aim Alzheimer's disease (AD) is characterised by extracellular deposition of amyloid‐β (Aβ) in amyloid plaques and intracellular aggregation and accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs). Although several kinases have been identified to contribute to the pathological phosphorylation of tau, kinase‐targeted therapies for AD have not been successful in clinical trials. Critically, the kinases responsible for numerous identified tau phosphorylation sites remain unknown. G protein‐coupled receptor (GPCR) kinases (GRKs) have recently been implicated in phosphorylation of non‐GPCR substrates, for example, tubulin and α‐synuclein, and in neurological disorders, including schizophrenia and Parkinson's disease. Accordingly, we investigated the involvement of GRKs in the pathophysiology of AD. Methods We performed a comprehensive immunohistochemical and biochemical analysis of the ubiquitously expressed GRKs, namely, GRK2, 3, 5 and 6, in postmortem human brain tissue of control subjects and AD patients. Results GRKs display unique cell‐type‐specific expression patterns in neurons, astrocytes and microglia. Levels of GRKs 2, 5 and 6 are specifically decreased in the CA1 region of the AD hippocampus. Biochemical evidence indicates that the GRKs differentially associate with total, soluble and insoluble pools of tau in the AD brain. Complementary immunohistochemical studies indicate that the GRKs differentially colocalise with total tau, phosphorylated tau and NFTs. Notably, GRKs 3 and 5 also colocalise with amyloid plaques. Conclusion These studies establish a link between GRKs and the pathological phosphorylation and accumulation of tau and amyloid pathology in AD brains and suggest a novel role for these kinases in regulation of the pathological hallmarks of AD.

Biased G protein–coupled receptor (GPCR) ligands, which preferentially activate G protein or β-arrestin signaling pathways, are leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer’s disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated β-arrestin signaling modulates amyloid-β (Aβ) generation in vitro and that Gpr3 deficiency ameliorates Aβ pathology in vivo . However, Gpr3 -deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein signaling. Here, we generated a G protein–biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated β-arrestin signaling in vivo . In contrast to Gpr3 -deficient mice, G protein–biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein–biased signaling reduces soluble Aβ levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical App NL-G-F AD mouse model. The changes in amyloid pathology are accompanied by robust microglial and astrocytic hypertrophy, which suggest a protective glial response that may limit amyloid plaque development in G protein–biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and β-arrestin signaling produce discrete and separable effects and provide proof of concept for the development of safer GPCR-targeting therapeutics with more directed pharmacological action for AD.

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Seasonality, in the context of emergency room (ER) admissions, can be described as the periodic incidence of disease, corresponding to seasons, or other pre-established calendar periods. Respiratory diseases, in general, show a seasonal pattern with incidence peak at the winter season, however research still presents a considerable amount of inconsistency. Incidence of cardiovascular diseases (CVD) is also very well linked to the cold season. Gastrointestinal, genitourinary and neurological diseases are poorly studied in regards their seasonal patterns. This study aimed to assess seasonality of the five categories of diseases-respiratory, cardiovascular, gastrointestinal, genitourinary, and neurological-using data from a community hospital in northwestern PA. We analyzed 14 years (2000-2014) of data from the Meadville Medical Center (MMC) ER admissions. For each ER admission case, we had information about ICD-9 code, sex, insurance, race, age and date, time and year of admission. Statistical analyses were performed using SAS 9.4 University version software. We found significantly fewer cases of respiratory diseases in spring (OR = 0.757), summer (OR = 0.579), and fall (OR = 0.741), when comparing to the winter season; however, seasonal differences were not found for cardiovascular, genitourinary, and neurological diseases. The implications of these results will primarily be used to improve Meadville's public health policies for cold seasons, and more specifically, implement programs that prepare the ER to receive and treat respiratory cases more efficiently in the cold season.

Background Alzheimer's Disease (AD) is characterized by pathological aggregation and accumulation of hyperphosphorylated microtubule‐associated protein tau1 in intracellular neurofibrillary tangles (NFTs)2,3. Phosphorylation is a vital cellular process associated with protein homeostasis and disease4. Tau, for instance, has more than 80 putative phosphorylation sites, which regulate both physiological and pathological tau functions1. Although several tau kinases have been identified to play causative roles in AD tau pathogenesis1,5, kinase‐targeted therapies for AD have been unsuccessful thus far6. Interestingly, the kinases responsible for several putative tau phosphorylation sites remain unknown7. G protein‐coupled receptor kinases (GRKs) are a family of seven kinases (GRKs 1‐7) that are implicated in numerous peripheral and brain pathologies8,9, including a cursory association of GRKs 2 and 5 with AD10. Nevertheless, a comprehensive characterization of the expression and distribution of GRKs in the non‐demented and AD human brain has not been previously performed. We hypothesize that establishment of the GRK profile and pattern in the human brain may provide insight into the putative involvement of GRKs in tau pathobiology in AD. Method We performed immunohistochemical and biochemical analysis of the four ubiquitously expressed GRKs (i.e., GRKs 2, 3, 5, and 6) in relation to the expression and accumulation of tau in postmortem human hippocampal tissue from control subjects and AD patients. Result Western blot analysis indicates that GRK levels are similar in control and AD brains. However, a region‐specific immunohistochemical analysis reveals that all four GRKs are decreased in the CA1 of the AD hippocampus, one of the most vulnerable regions to AD pathology11,12. Interestingly, the GRKs differentially co‐localize within total and phosphorylated tau NFT pathology. Additionally, all GRKs tend to positively correlate with soluble tau levels in the AD brain. Finally, GRKs 3 and 5 display a remarkable co‐localization with late‐stage NFTs in the AD brain. Conclusion Collectively, our findings show that the GRKs associate with tau pathology in AD brains, suggesting that GRKs may regulate tau phosphorylation, solubility, and aggregation in AD. These results provide a foundation for future mechanistic studies addressing the putative role of GRKs in tau physiology and pathology.