G protein‐coupled receptor kinases are associated with Alzheimer's disease pathology

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. Kinase‐targeted therapies for Alzheimer’s disease (AD) have failed thus far. Using biochemical and Immunohistochemical analyses of postmortem human brain samples, we report a novel role for the family of G protein‐coupled receptor kinases (GRKs) in the pathophysiology of AD. We determine that GRK levels are reduced in the CA1 region of the hippocampus and are associated with the pathological phosphorylation and accumulation of tau and amyloid pathologies in AD. Collectively, our findings establish GRKs as putative therapeutic targets for AD.