Thais Rafael Guimarães1,2, Eric Swanson1,3, Julia Kofler4, Amantha Thathiah1,3,5. 1. Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 2. Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 3. Brain Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 4. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 5. Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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.
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.
Authors: Hansruedi Mathys; Jose Davila-Velderrain; Zhuyu Peng; Fan Gao; Shahin Mohammadi; Jennie Z Young; Madhvi Menon; Liang He; Fatema Abdurrob; Xueqiao Jiang; Anthony J Martorell; Richard M Ransohoff; Brian P Hafler; David A Bennett; Manolis Kellis; Li-Huei Tsai Journal: Nature Date: 2019-05-01 Impact factor: 49.962
Authors: Kelly N Nobles; Kunhong Xiao; Seungkirl Ahn; Arun K Shukla; Christopher M Lam; Sudarshan Rajagopal; Ryan T Strachan; Teng-Yi Huang; Erin A Bressler; Makoto R Hara; Sudha K Shenoy; Steven P Gygi; Robert J Lefkowitz Journal: Sci Signal Date: 2011-08-09 Impact factor: 8.192
Authors: Ian G McKeith; Bradley F Boeve; Dennis W Dickson; Glenda Halliday; John-Paul Taylor; Daniel Weintraub; Dag Aarsland; James Galvin; Johannes Attems; Clive G Ballard; Ashley Bayston; Thomas G Beach; Frédéric Blanc; Nicolaas Bohnen; Laura Bonanni; Jose Bras; Patrik Brundin; David Burn; Alice Chen-Plotkin; John E Duda; Omar El-Agnaf; Howard Feldman; Tanis J Ferman; Dominic Ffytche; Hiroshige Fujishiro; Douglas Galasko; Jennifer G Goldman; Stephen N Gomperts; Neill R Graff-Radford; Lawrence S Honig; Alex Iranzo; Kejal Kantarci; Daniel Kaufer; Walter Kukull; Virginia M Y Lee; James B Leverenz; Simon Lewis; Carol Lippa; Angela Lunde; Mario Masellis; Eliezer Masliah; Pamela McLean; Brit Mollenhauer; Thomas J Montine; Emilio Moreno; Etsuro Mori; Melissa Murray; John T O'Brien; Sotoshi Orimo; Ronald B Postuma; Shankar Ramaswamy; Owen A Ross; David P Salmon; Andrew Singleton; Angela Taylor; Alan Thomas; Pietro Tiraboschi; Jon B Toledo; John Q Trojanowski; Debby Tsuang; Zuzana Walker; Masahito Yamada; Kenji Kosaka Journal: Neurology Date: 2017-06-07 Impact factor: 9.910
Authors: Nicholas K Todd; Yunhong Huang; Ji Young Lee; Pemra Doruker; James M Krieger; Ryan Salisbury; Matthew MacDonald; Ivet Bahar; Amantha Thathiah Journal: Cell Rep Date: 2022-07-19 Impact factor: 9.995