Inhibition of CK2 mitigates Alzheimer’s tau pathology by preventing NR2B synaptic mislocalization

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that exhibits pathological changes in both tau and synaptic function. AD patients display increases in hyperphosphorylated tau and synaptic activity. Previous studies have individually identified the role of NR2B subunit-containing NMDA receptors in AD related synaptic dysfunction and aggregated tau without reconciling the conflicting differences and implications of NR2B expression. Inhibition of extrasynaptically located NR2B mitigates tau pathology in AD models, whereas the inhibition of synaptic NR2B replicates tau-associated hyperactivity. This suggests that a simultaneous increase in extrasynaptic NR2B and decrease in synaptic NR2B may be responsible for tau pathology and synaptic dysfunction, respectively. The synaptic location of NR2B is regulated by casein kinase 2 (CK2), which is highly expressed in AD patients. Here, we used patient brains diagnosed with AD, corticobasal degeneration, progressive supranuclear palsy or Pick’s disease to characterize CK2 expression across these diverse tauopathies. Human derived material was also utilized in conjunction with cultured hippocampal neurons in order to investigate AD-induced changes in NR2B location. We further assessed the therapeutic effect of CK2 inhibition on NR2B synaptic distribution and tau pathology. We found that aberrant expression of CK2, and synaptically translocated NR2B, is unique to AD patients compared to other tauopathies. Increased CK2 was also observed in AD-tau treated neurons in addition to the mislocalization of NR2B receptors. Tau burden was alleviated in vitro by correcting synaptic:extrasynaptic NR2B function. Restoring NR2B physiological expression patterns with CK2 inhibition and inhibiting the function of excessive extrasynaptic NR2B with Memantine both mitigated tau accumulation in vitro. However, the combined pharmacological treatment promoted the aggregation of tau. Our data suggests that the synaptic:extrasynaptic balance of NR2B function regulates AD-tau pathogenesis, and that the inhibition of CK2, and concomitant prevention of NR2B mislocalization, may be a useful therapeutic tool for AD patients.

Thirty years of SET/TAF1β/I2PP2A: from the identification of the biological functions to its implications in cancer and Alzheimer’s disease

“…As Ser9 phosphorylation triggers not only SET translocation to the cytosol but it also increases the affinity between SET and PP2A (30), strategies to target this phosphorylation might provide a novel therapeutic approach for cancer and AD (98). A recent study shows that CK2 pharmacological inhibition reduces the accumulation of tau in vitro, but whether these effects are mediated by SET exclusion from the cytosol and whether this inhibition would ameliorate AD symptoms in vivo is not known (136). In AML models, CK2 genetic silencing and pharmacological inhibition did not result in Cyclin B-CDK1 Regulation of cell cycle (62) Cytochrome c Inhibition of SET (137) E-CDK2-p21 complex Regulation of cell cycle (61) Estrogen Receptor (ER) Inhibition of transcription of downstream targets (41,42) FOXO1 Inhibition of transcription of downstream targets (26) Glucocorticoid receptor (GR) Inhibition of transcription of downstream targets (41) Granzyme A Induction of apoptosis (65,66) Histone H1 Regulation of transcription (42) Histone H2A Regulation of transcription (138) Histone H2B Regulation of transcription (25,138) Histone H3 Regulation of transcription (15,(23)(24)(25) Histone H4 Regulation of transcription (38) hnRNPA2 Cytosolic retention of SET (97,102) Jcasp fragment Inducing neuronal death (64) KAP1 Repression of DNA damage repair by HR (49) KLF5 Inhibition of transcription of downstream targets (27) KMT2A Transcription activation of downstream target genes (43,79) Ku70 Prevention of DNA damage repair by NHEJ (48) PIKE-L Cytosolic retention of SET (122) PP2A Inhibition of PP2A activity (16,21,52) p21Cip1 Inhibition p21/Regulation of cell cycle (61) p53 Inhibition of transcription o...…”

Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington’s Disease

“…Contrary to what was proposed in HD, CK2 contributes to NR2B phosphorylation and to a detrimental imbalance in NR2B synaptic/extrasynaptic ratio in AD, which is also associated with tau accumulation [ 170 ]. In addition, CK2 participates in the secretion of pro-inflammatory cytokines, assessed in human astrocytes, and was suggested to modulate neuroinflammation in AD, although the mechanism by which CK2 participates in such process is unclear [ 163 ].…”

“…In addition, PSD-95 itself is a CK2 substrate [ 167 ]. Extensive studies have addressed the role of CK2 in the regulation of NMDARs in various contexts [ 167 , 168 , 169 , 170 , 171 ], although our knowledge of such regulation in HD and whether there is a differential contribution between CK2α and CK2α’, remains limited. Pharmacological inhibition of CK2 in primary neurons from YAC128 mice co-expressing NMDAR and human Htt-Q138 exacerbated NMDAR-mediated excitotoxicity and suggested a protective role of CK2 in preventing excitotoxic damage [ 129 ].…”

Kinases and Their Potential as Therapeutic Targets in Huntington’s Disease

“…Contrary to what was proposed in HD, CK2 contributes to NR2B phosphorylation and to a detrimental imbalance in NR2B synaptic/extrasynaptic ratio in AD, which is also associated with tau accumulation [174]. In addition, CK2 participates in the secretion of pro-inflammatory cytokines, assessed in human astrocytes, and was suggested to modulate neuroinflammation in AD, although the mechanism by which CK2 participates in such process is unclear [167].…”

“…In addition, PSD-95 itself is a CK2 substrate [171]. Extensive studies have addressed the role of CK2 in the regulation of NMDARs in various contexts [171][172][173][174][175], although our knowledge of such regulation in HD and whether there is a differential contribution between CK2α and CK2α', remains limited. Pharmacological inhibition of CK2 in primary neurons from YAC128 mice coexpressing NMDAR and human Htt-Q138 exacerbated NMDAR-mediated excitotoxicity and suggested a protective role of CK2 in preventing excitotoxic damage [132].…”