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Association of G protein‐coupled receptor kinases with tau pathology in Alzheimer's disease
Author(s) -
Guimaraes Thais Rafael,
Swanson Eric,
Kofler Julia,
Thathiah Amantha
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047492
Subject(s) - g protein coupled receptor kinase , kinase , biology , phosphorylation , tau protein , tauopathy , microbiology and biotechnology , neuroscience , pathology , alzheimer's disease , g protein coupled receptor , disease , medicine , signal transduction , neurodegeneration
Background Alzheimer's Disease (AD) is characterized by pathological aggregation and accumulation of hyperphosphorylated microtubule‐associated protein tau 1 in intracellular neurofibrillary tangles (NFTs) 2,3 . Phosphorylation is a vital cellular process associated with protein homeostasis and disease 4 . Tau, for instance, has more than 80 putative phosphorylation sites, which regulate both physiological and pathological tau functions 1 . Although several tau kinases have been identified to play causative roles in AD tau pathogenesis 1,5 , kinase‐targeted therapies for AD have been unsuccessful thus far 6 . Interestingly, the kinases responsible for several putative tau phosphorylation sites remain unknown 7 . G protein‐coupled receptor kinases (GRKs) are a family of seven kinases (GRKs 1‐7) that are implicated in numerous peripheral and brain pathologies 8,9 , including a cursory association of GRKs 2 and 5 with AD 10 . 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 pathology 11,12 . 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.