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

Abstract

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.

GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation

“…In agreement with these data, we observe a decrease in constitutive g-secretase activity and Ab generation in both the GRK3 KO and GRK5 KO cells in comparison with control cells, which suggests that GRK3 and GRK5 activity contributes to increased g-secretase activity and Ab generation. Interestingly, our lab recently determined that both GRK3 and GRK5 are abundantly localized around amyloid plaques in human AD brains (Guimarães et al, 2021). Together, these data support the hypothesis that GRK3 and GRK5 activity may contribute to pathogenic Ab generation while GRK2 activity may act in a protective manner to regulate g-secretase activity.…”

The landscape of m6A regulators in multiple brain regions of Alzheimer's Disease

“…In addition, we also found multiple G protein-related signaling pathways changed in patients' brains in an m6A-related way. The effect of G protein receptor-coupled kinases on AD pathology has been reported [43]. FTO, RBM15, YTHDF2, YTHDF3, YTHDC3, HNRNPC, and HNRNPA2B1 were found to play important roles in different brain regions.…”

NEU1—A Unique Therapeutic Target for Alzheimer’s Disease

“…Studies have also indicated that the pattern of expression of the GRKs in neurons is cell type-specific in the human brain in AD subjects. Additionally, an overall positive correlation has been established between GRKs 2, 3, and 6 and soluble tau found in the AD brain ( Guimaraes et al, 2021 ). Furthermore, it has been suggested that these kinases may have direct or indirect involvement in the altered tau solubility, tau phosphorylation, as well as tau aggregation.…”

“…However, evidence shows that GRKs are also associated with phosphorylation of non-GPCR proteins to manipulate various other cellular responses besides GPCR-dependent mechanisms. GRKs have also been reported to be involved in the pathological phosphorylation and accumulation of tau and amyloid pathology in AD brains ( Guimaraes et al, 2021 ). Studies have suggested their unique role in the pathological processes involved in AD, and thus, they can be a potential therapeutic target.…”