The roles of RACK1 in the pathogenesis of Alzheimer's disease

Abstract

The receptor for activated C kinase 1 (RACK1) is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease (AD), a prevalent neurodegenerative disease. RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD. Specifically, RACK1 is involved in regulation of the amyloid-β precursor protein processing through α- or β-secretase by binding to different protein kinase C isoforms. Additionally, RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors, thereby preventing neuronal excitotoxicity. RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways, such as nuclear factor-kappa B, tumor necrosis factor-alpha, and NOD-like receptor family pyrin domain-containing 3 pathways. The potential to design therapeutics that block amyloid-β accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy, in which RACK1 is a potential target. In this review, we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.

Keywords

RACK1 / Alzheimer's disease / PKC / amyloid-β / synaptic plasticity / neuroinflammation

Fundings

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82071395), the Natural Science Foundation of Chongqing (Grant Nos. cstc2021ycjh-bgzxm0186, cstc2020jcyj-zdxmX0004, and cstc2021jcyj-bsh0023) and the CQMU Program for Youth Innovation in Future Medicine (Grant No. W0044).

Acknowledgments

None.

References

[1] Torrisi SA, Geraci F, Tropea MR, et al. Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by Aβ_1-42 oligomers in mice: a key role of transforming growth factor-β1[J]. Front Pharmacol, 2019, 10: 693. doi: 10.3389/fphar.2019.00693

[2] Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease[J]. Lancet, 2021, 397(10284): 1577-1590. doi: 10.1016/S0140-6736(20)32205-4

[3] Morgen K, Frölich L. The metabolism hypothesis of Alzheimer's disease: from the concept of central insulin resistance and associated consequences to insulin therapy[J]. J Neural Transm, 2015, 122(4): 499-504. doi: 10.1007/s00702-015-1377-5

[4] Wang M, Miao D, Cao X, et al. Innate immune activation in Alzheimer's disease[J]. Ann Transl Med, 2018, 6(10): 177. doi: 10.21037/atm.2018.04.20

[5] Sharma D, Kanneganti TD. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation[J]. J Cell Biol, 2016, 213(6): 617-629. doi: 10.1083/jcb.201602089

[6] Battaini F, Pascale A, Paoletti R, et al. The role of anchoring protein RACK1 in PKC activation in the ageing rat brain[J]. Trends Neurosci, 1997, 20(9): 410-415. doi: 10.1016/S0166-2236(97)01084-9

[7] Buoso E, Galasso M, Serafini MM, et al. Transcriptional regulation of RACK1 and modulation of its expression: role of steroid hormones and significance in health and aging[J]. Cell Signal, 2017, 35: 264-271. doi: 10.1016/j.cellsig.2017.02.010

[8] Besson A, Wilson TL, Yong VW. The anchoring protein RACK1 links protein kinase Cε to integrin β chains. Requirement for adhesion and motility[J]. J Biol Chem, 2002, 277(24): 22073-22084. doi: 10.1074/jbc.M111644200

[9] Slager RE, Devasure JM, Pavlik JA, et al. RACK1, a PKC targeting protein, is exclusively localized to basal airway epithelial cells[J]. J Histochem Cytochem, 2008, 56(1): 7-14. doi: 10.1369/jhc.7A7249.2007

[10] Pass JM, Gao J, Jones WK, et al. Enhanced PKCβII translocation and PKCβII-RACK1 interactions in PKCε-induced heart failure: a role for RACK1[J]. Am J Physiol Heart Circ Physiol, 2001, 281(6): H2500-H2510. doi: 10.1152/ajpheart.2001.281.6.H2500

[11] Grosso S, Volta V, Sala LA, et al. PKCβII modulates translation independently from mTOR and through RACK1[J]. Biochem J, 2008, 415(1): 77-85. doi: 10.1042/BJ20080463

[12] Pass JM, Zheng Y, Wead WB, et al. PKCε activation induces dichotomous cardiac phenotypes and modulates PKCε-RACK interactions and RACK expression[J]. Am J Physiol Heart Circ Physiol, 2001, 280(3): H946-H955. doi: 10.1152/ajpheart.2001.280.3.H946

[13] Schechtman D, Mochly-Rosen D. Adaptor proteins in protein kinase C-mediated signal transduction[J]. Oncogene, 2001, 20(44): 6339-6347. doi: 10.1038/sj.onc.1204778

[14] Lei J, Li Q, Gao Y, et al. Increased PKCα activity by Rack1 overexpression is responsible for chemotherapy resistance in T-cell acute lymphoblastic leukemia-derived cell line[J]. Sci Rep, 2016, 6: 33717. doi: 10.1038/srep33717

[15] Osmanagic-Myers S, Wiche G. Plectin-RACK1 (receptor for activated C kinase 1) scaffolding: a novel mechanism to regulate protein kinase C activity[J]. J Biol Chem, 2004, 279(18): 18701-18710. doi: 10.1074/jbc.M312382200

[16] Chen YH, Wang HC, Lin CY, et al. Effects of prenyl pyrophosphates on the binding of PKCγ with RACK1[J]. J Exp Zool A Comp Exp Biol, 2003, 295A(1): 71-82. doi: 10.1002/jez.a.10213

[17] Dell EJ, Connor J, Chen S, et al. The βγ subunit of heterotrimeric G proteins interacts with RACK1 and two other WD repeat proteins[J]. J Biol Chem, 2002, 277(51): 49888-49895. doi: 10.1074/jbc.M202755200

[18] Patterson RL, van Rossum DB, Barrow RK, et al. RACK1 binds to inositol 1, 4, 5-trisphosphate receptors and mediates Ca²⁺ release[J]. Proc Natl Acad Sci U S A, 2004, 101(8): 2328-2332. doi: 10.1073/pnas.0308567100

[19] Rodriguez MM, Ron D, Touhara K, et al. RACK1, a protein kinase C anchoring protein, coordinates the binding of activated protein kinase C and select pleckstrin homology domains in vitro[J]. Biochemistry, 1999, 38(42): 13787-13794. doi: 10.1021/bi991055k

[20] Brandon NJ, Uren JM, Kittler JT, et al. Subunit-specific association of protein kinase C and the receptor for activated C kinase with GABA type A receptors[J]. J Neurosci, 1999, 19(21): 9228-9234. doi: 10.1523/JNEUROSCI.19-21-09228.1999

[21] Yaka R, Thornton C, Vagts AJ, et al. NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1[J]. Proc Natl Acad Sci U S A, 2002, 99(8): 5710-5715. doi: 10.1073/pnas.062046299

[22] Adams DR, Ron D, Kiely PA. RACK1, A multifaceted scaffolding protein: structure and function[J]. Cell Commun Signal, 2011, 9: 22. doi: 10.1186/1478-811X-9-22

[23] Van der Zee EA, Palm IF, O'Connor M, et al. Aging-related alterations in the distribution of Ca²⁺-dependent PKC isoforms in rabbit hippocampus[J]. Hippocampus, 2004, 14(7): 849-860. doi: 10.1002/hipo.20000

[24] Pascale A, Fortino I, Govoni S, et al. Functional impairment in protein kinase C by RACK1 (receptor for activated C kinase 1) deficiency in aged rat brain cortex[J]. J Neurochem, 1996, 67(6): 2471-2477. doi: 10.1046/j.1471-4159.1996.67062471.x

[25] Peyrl A, Weitzdoerfer R, Gulesserian T, et al. Aberrant expression of signaling-related proteins 14-3-3 gamma and RACK1 in fetal down syndrome brain (trisomy 21)[J]. Electrophoresis, 2002, 23(1): 152-157. doi: 10.1002/1522-2683(200201)23:1<152::AID-ELPS152>3.0.CO;2-T

[26] Alkon DL, Sun MK, Nelson TJ. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease[J]. Trends Pharmacol Sci, 2007, 28(2): 51-60. doi: 10.1016/j.tips.2006.12.002

[27] Ni H, Rui Q, Xu Y, et al. RACK1 upregulation induces neuroprotection by activating the IRE1-XBP1 signaling pathway following traumatic brain injury in rats[J]. Exp Neurol, 2018, 304: 102-113. doi: 10.1016/j.expneurol.2018.03.003

[28] Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective[J]. Cell, 2005, 120(4): 545-555. doi: 10.1016/j.cell.2005.02.008

[29] Zhu J, Chen X, Song Y, et al. Deficit of RACK1 contributes to the spatial memory impairment via upregulating BECLIN1 to induce autophagy[J]. Life Sci, 2016, 151: 115-121. doi: 10.1016/j.lfs.2016.02.014

[30] Wang X, Zhou X, Li G, et al. Modifications and trafficking of APP in the pathogenesis of Alzheimer's disease[J]. Front Mol Neurosci, 2017, 10: 294. doi: 10.3389/fnmol.2017.00294

[31] Kögel D, Deller T, Behl C. Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging[J]. Exp Brain Res, 2012, 217(3-4): 471-479. doi: 10.1007/s00221-011-2932-4

[32] Turner PR, O'Connor K, Tate WP, et al. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory[J]. Prog Neurobiol, 2003, 70(1): 1-32. doi: 10.1016/S0301-0082(03)00089-3

[33] Fol R, Braudeau J, Ludewig S, et al. Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer's disease mouse model[J]. Acta Neuropathol, 2016, 131(2): 247-266. doi: 10.1007/s00401-015-1498-9

[34] Hampel H, Hardy J, Blennow K, et al. The amyloid-β pathway in Alzheimer's disease[J]. Mol Psychiatry, 2021, 26(10): 5481-5503. doi: 10.1038/s41380-021-01249-0

[35] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics[J]. Science, 2002, 297(5580): 353-356. doi: 10.1126/science.1072994

[36] de Barry J, Liégeois CM, Janoshazi A. Protein kinase C as a peripheral biomarker for Alzheimer's disease[J]. Exp Gerontol, 2010, 45(1): 64-69. doi: 10.1016/j.exger.2009.10.015

[37] Shimohama S, Kamiya S, Taniguchi T, et al. Intracellular receptors for activated C-kinase in the postmortem human brain: no alteration in Alzheimer disease[J]. Alzheimer Dis Assoc Disord, 1998, 12(4): 384-386. doi: 10.1097/00002093-199812000-00022

[38] He W, Tu M, Du Y, et al. Nicotine promotes AβPP nonamyloidogenic processing via RACK1-dependent activation of PKC in SH-SY5Y-AβPP695 cells[J]. J Alzheimers Dis, 2020, 75(2): 451-460. doi: 10.3233/JAD-200003

[39] Sato N, Shinohara M, Rakugi H, et al. Dual effects of statins on Aβ metabolism: upregulation of the degradation of APP-CTF and Aβ clearance[J]. Neurodegener Dis, 2012, 10(1-4): 305-308. doi: 10.1159/000334534

[40] Buoso E, Biundo F, Lanni C, et al. Modulation of Rack-1/PKCβII signalling by soluble AβPPα in SH-SY5Y cells[J]. Curr Alzheimer Res, 2013, 10(7): 697-705. doi: 10.2174/15672050113109990145

[41] Lee W, Boo JH, Jung MW, et al. Amyloid beta peptide directly inhibits PKC activation[J]. Mol Cell Neurosci, 2004, 26(2): 222-231. doi: 10.1016/j.mcn.2003.10.020

[42] Cheng G, Yu Z, Zhou D, et al. Phosphatidylinositol-3-kinase-Akt kinase and p42/p44 mitogen-activated protein kinases mediate neurotrophic and excitoprotective actions of a secreted form of amyloid precursor protein[J]. Exp Neurol, 2002, 175(2): 407-414. doi: 10.1006/exnr.2002.7920

[43] Mattson MP, Camandola S. NF-κB in neuronal plasticity and neurodegenerative disorders[J]. J Clin Invest, 2001, 107(3): 247-254. doi: 10.1172/JCI11916

[44] Thal DR, Rüb U, Orantes M, et al. Phases of Aβ-deposition in the human brain and its relevance for the development of AD[J]. Neurology, 2002, 58(12): 1791-1800. doi: 10.1212/WNL.58.12.1791

[45] Liu W, Dou F, Feng J, et al. RACK1 is involved in β-amyloid impairment of muscarinic regulation of GABAergic transmission[J]. Neurobiol Aging, 2011, 32(10): 1818-1826. doi: 10.1016/j.neurobiolaging.2009.10.017

[46] Saito M, Iwawaki T, Taya C, et al. Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice[J]. Nat Biotechnol, 2001, 19(8): 746-750. doi: 10.1038/90795

[47] Favit A, Grimaldi M, Nelson TJ, et al. Alzheimer's-specific effects of soluble β-amyloid on protein kinase C-α and -γ degradation in human fibroblasts[J]. Proc Nat Acad Sci U S A, 1998, 95(10): 5562-5567. doi: 10.1073/pnas.95.10.5562

[48] Choi DS, Wang D, Yu G, et al. PKCε increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice[J]. Proc Natl Acad Sci U S A, 2006, 103(21): 8215-8220. doi: 10.1073/pnas.0509725103

[49] Zhu G, Wang D, Lin YH, et al. Protein kinase Cϵ suppresses Aβ production and promotes activation of α-secretase[J]. Biochem Biophys Res Commun, 2001, 285(4): 997-1006. doi: 10.1006/bbrc.2001.5273

[50] Du Y, Zhao Y, Li C, et al. Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes[J]. J Exp Med, 2018, 215(6): 1665-1677. doi: 10.1084/jem.20171193

[51] Sajan MP, Hansen BC, Higgs MG, et al. Atypical PKC, PKCλ/ι activates β-secretase and increases Aβ_1-40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease[J]. Neurobiol Aging, 2018, 61: 225-237. doi: 10.1016/j.neurobiolaging.2017.09.001

[52] Mazanetz MP, Fischer PM. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases[J]. Nat Rev Drug Discov, 2007, 6(6): 464-479. doi: 10.1038/nrd2111

[53] Takashima A. GSK-3 is essential in the pathogenesis of Alzheimer's disease[J]. J Alzheimers Dis, 2006, 9(S3): 309-317. doi: 10.3233/JAD-2006-9S335

[54] Hanseeuw BJ, Betensky RA, Jacobs HIL, et al. Association of amyloid and tau with cognition in preclinical alzheimer disease: a longitudinal study[J]. JAMA Neurol, 2019, 76(8): 915-924. doi: 10.1001/jamaneurol.2019.1424

[55] Isagawa T, Mukai H, Oishi K, et al. Dual effects of PKNα and protein kinase C on phosphorylation of tau protein by glycogen synthase kinase-3β[J]. Biochem Biophys Res Commun, 2000, 273(1): 209-212. doi: 10.1006/bbrc.2000.2926

[56] Zhang D, Wang Q, Zhu T, et al. RACK1 promotes the proliferation of THP1 acute myeloid leukemia cells[J]. Mol Cell Biochem, 2013, 384(1-2): 197-202. doi: 10.1007/s11010-013-1798-0

[57] Collingridge GL, Isaac JTR, Wang Y. Receptor trafficking and synaptic plasticity[J]. Nat Rev Neurosci, 2004, 5(12): 952-962. doi: 10.1038/nrn1556

[58] Lau CG, Takeuchi K, Rodenas-Ruano A, et al. Regulation of NMDA receptor Ca²⁺ signalling and synaptic plasticity[J]. Biochem Soc Trans, 2009, 37(Pt 6): 1369-1374.

[59] Hansen KB, Yi F, Perszyk RE, et al. Structure, function, and allosteric modulation of NMDA receptors[J]. J Gen Physiol, 2018, 150(8): 1081-1105. doi: 10.1085/jgp.201812032

[60] Petit-Pedrol M, Groc L. Regulation of membrane NMDA receptors by dynamics and protein interactions[J]. J Cell Biol, 2021, 220(1): e202006101. doi: 10.1083/jcb.202006101

[61] Kojima N, Wang J, Mansuy IM, et al. Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene[J]. Proc Natl Acad Sci U S A, 1997, 94(9): 4761-4765. doi: 10.1073/pnas.94.9.4761

[62] Thornton C, Tang KC, Phamluong K, et al. Spatial and temporal regulation of RACK1 function and N-methyl-D-aspartate receptor activity through WD40 motif-mediated dimerization[J]. J Biol Chem, 2004, 279(30): 31357-31364. doi: 10.1074/jbc.M402316200

[63] Yaka R, Phamluong K, Ron D. Scaffolding of Fyn kinase to the NMDA receptor determines brain region sensitivity to ethanol[J]. J Neurosci, 2003, 23(9): 3623-3632. doi: 10.1523/JNEUROSCI.23-09-03623.2003

[64] Wang J, Carnicella S, Phamluong K, et al. Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior[J]. J Neurosci, 2007, 27(13): 3593-3602. doi: 10.1523/JNEUROSCI.4749-06.2007

[65] Phamluong K, Darcq E, Wu S, et al. Fyn signaling is compartmentalized to dopamine D1 receptor expressing neurons in the dorsal medial striatum[J]. Front Mol Neurosci, 2017, 10: 273. doi: 10.3389/fnmol.2017.00273

[66] Raymond CR, Redman SJ. Different calcium sources are narrowly tuned to the induction of different forms of LTP[J]. J Neurophysiol, 2002, 88(1): 249-255. doi: 10.1152/jn.2002.88.1.249

[67] Ambrad Giovannetti E, Fuhrmann M. Unsupervised excitation: GABAergic dysfunctions in Alzheimer's disease[J]. Brain Res, 2019, 1707: 216-226. doi: 10.1016/j.brainres.2018.11.042

[68] Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease[J]. Nat Rev Neurosci, 2016, 17(12): 777-792. doi: 10.1038/nrn.2016.141

[69] Samakashvili S, Ibáñez C, Simó C, et al. Analysis of chiral amino acids in cerebrospinal fluid samples linked to different stages of Alzheimer disease[J]. Electrophoresis, 2011, 32(19): 2757-2764. doi: 10.1002/elps.201100139

[70] Yoshiike Y, Kimura T, Yamashita S, et al. GABA_A receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin[J]. PLoS One, 2008, 3(8): e3029. doi: 10.1371/journal.pone.0003029

[71] Brandon NJ, Jovanovic JN, Smart TG, et al. Receptor for activated C kinase-1 facilitates protein kinase C-dependent phosphorylation and functional modulation of GABA_A receptors with the activation of G-protein-coupled receptors[J]. J Neurosci, 2002, 22(15): 6353-6361. doi: 10.1523/JNEUROSCI.22-15-06353.2002

[72] Meier J, Akyeli J, Kirischuk S, et al. GABA_A receptor activity and PKC control inhibitory synaptogenesis in CNS tissue slices[J]. Mol Cell Neurosci, 2003, 23(4): 600-613. doi: 10.1016/S1044-7431(03)00079-4

[73] Feng J, Cai X, Zhao J, et al. Serotonin receptors modulate GABA_A receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons[J]. J Neurosci, 2001, 21(17): 6502-6511. doi: 10.1523/JNEUROSCI.21-17-06502.2001

[74] Littlejohn EL, Boychuk CR. Protein kinase C-dependent effects of neurosteroids on synaptic GABA_A receptor inhibition require the δ-subunit[J]. Front Physiol, 2021, 12: 742838. doi: 10.3389/fphys.2021.742838

[75] Chen J, He Y, Wu Y, et al. Single ethanol withdrawal regulates extrasynaptic δ-GABA_A receptors via PKCδ activation[J]. Front Mol Neurosci, 2018, 11: 141. doi: 10.3389/fnmol.2018.00141

[76] Li Q, Li Q, Jia J, et al. Sodium valproate ameliorates neuronal apoptosis in a kainic acid model of epilepsy via enhancing PKC-dependent GABA_AR γ2 serine 327 phosphorylation[J]. Neurochem Res, 2018, 43(12): 2343-2352. doi: 10.1007/s11064-018-2659-8

[77] Weerasinghe-Mudiyanselage PDE, Ang MJ, Kang S, et al. Structural plasticity of the hippocampus in neurodegenerative diseases[J]. Int J Mol Sci, 2022, 23(6): 3349. doi: 10.3390/ijms23063349

[78] Mufson EJ, Mahady L, Waters D, et al. Hippocampal plasticity during the progression of Alzheimer's disease[J]. Neuroscience, 2015, 309: 51-67. doi: 10.1016/j.neuroscience.2015.03.006

[79] Kershner L, Welshhans K. RACK1 is necessary for the formation of point contacts and regulates axon growth[J]. Dev Neurobiol, 2017, 77(9): 1038-1056. doi: 10.1002/dneu.22491

[80] Kershner L, Welshhans K. RACK1 regulates neural development[J]. Neural Regen Res, 2017, 12(7): 1036-1039. doi: 10.4103/1673-5374.211175

[81] Sklan EH, Podoly E, Soreq H. RACK1 has the nerve to act: structure meets function in the nervous system[J]. Prog Neurobiol, 2006, 78(2): 117-134. doi: 10.1016/j.pneurobio.2005.12.002

[82] Yang H, Yang C, Zhu Q, et al. Rack1 controls parallel fiber-purkinje cell synaptogenesis and synaptic transmission[J]. Front Cell Neurosci, 2019, 13: 539. doi: 10.3389/fncel.2019.00539

[83] Li H, Shang J, Zhang C, et al. Repetitive transcranial magnetic stimulation alleviates neurological deficits after cerebral ischemia through interaction between RACK1 and BDNF exon IV by the phosphorylation-dependent factor MeCP2[J]. Neurotherapeutics, 2020, 17(2): 651-663. doi: 10.1007/s13311-019-00771-y

[84] Ceci M, Welshhans K, Ciotti MT, et al. RACK1 is a ribosome scaffold protein for β-actin mRNA/ZBP1 complex[J]. PLoS One, 2012, 7(4): e35034. doi: 10.1371/journal.pone.0035034

[85] Dwane S, Durack E, O'Connor R, et al. RACK1 promotes neurite outgrowth by scaffolding AGAP2 to FAK[J]. Cell Signal, 2014, 26(1): 9-18. doi: 10.1016/j.cellsig.2013.08.036

[86] Ju Hwang C, Choi DY, Park MH, et al. NF-κB as a key mediator of brain inflammation in Alzheimer's disease[J]. CNS Neurol Disord Drug Targets, 2019, 18(1): 3-10. doi: 10.2174/1871527316666170807130011

[87] Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease[J]. Nat Rev Neurosci, 2015, 16(6): 358-372. doi: 10.1038/nrn3880

[88] Morgan MJ, Liu Z. Crosstalk of reactive oxygen species and NF-κB signaling[J]. Cell Res, 2011, 21(1): 103-115. doi: 10.1038/cr.2010.178

[89] Chami L, Buggia-Prévot V, Duplan E, et al. Nuclear factor-κB regulates βAPP and β- and γ-secretases differently at physiological and supraphysiological Aβ concentrations[J]. J Biol Chem, 2012, 287(29): 24573-24584. doi: 10.1074/jbc.M111.333054

[90] Waiskopf N, Ofek K, Gilboa-Geffen A, et al. AChE and RACK1 promote the anti-inflammatory properties of fluoxetine[J]. J Mol Neurosci, 2014, 53(3): 306-315. doi: 10.1007/s12031-013-0174-6

[91] Birikh KR, Sklan EH, Shoham S, et al. Interaction of "readthrough" acetylcholinesterase with RACK1 and PKCβⅡ correlates with intensified fear-induced conflict behavior[J]. Proc Natl Acad Sci U S A, 2003, 100(1): 283-288. doi: 10.1073/pnas.0135647100

[92] Nijholt I, Farchi N, Kye M, et al. Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation[J]. Mol Psychiatry, 2004, 9(2): 174-183. doi: 10.1038/sj.mp.4001446

[93] Yin H, Song S, Pan X. Knockdown of miR-155 protects microglia against LPS-induced inflammatory injury via targeting RACK1: a novel research for intracranial infection[J]. J Inflamm, 2017, 14: 17. doi: 10.1186/s12950-017-0162-7

[94] Teng Y, Zhang M, Wang W, et al. Compound danshen tablet ameliorated aβ_25-35-induced spatial memory impairment in mice via rescuing imbalance between cytokines and neurotrophins[J]. BMC Complement Altern Med, 2014, 14: 23. doi: 10.1186/1472-6882-14-23

[95] Chou W, Guo Z, Guo H, et al. AIM2 in regulatory T cells restrains autoimmune diseases[J]. Nature, 2021, 591(7849): 300-305. doi: 10.1038/s41586-021-03231-w

[96] Wang Q, Zhou S, Wang J, et al. RACK1 antagonizes TNF-α-induced cell death by promoting p38 activation[J]. Sci Rep, 2015, 5: 14298. doi: 10.1038/srep14298

[97] Duan Y, Zhang L, Angosto-Bazarra D, et al. RACK 1 mediates NLRP3 inflammasome activation by promoting NLRP3 active conformation and inflammasome assembly[J]. Cell Rep, 2020, 33(7): 108405. doi: 10.1016/j.celrep.2020.108405

[98] Buoso E, Masi M, Galbiati V, et al. Effect of estrogen-active compounds on the expression of RACK1 and immunological implications[J]. Arch Toxicol, 2020, 94(6): 2081-2095. doi: 10.1007/s00204-020-02756-9

[99] Khan TK, Alkon DL. An internally controlled peripheral biomarker for Alzheimer's disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin[J]. Proc Natl Acad Sci U S A, 2006, 103(35): 13203-13207. doi: 10.1073/pnas.0605411103

[100] Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice[J]. Nature, 2013, 493(7434): 674-678. doi: 10.1038/nature11729

[101] Qu Z, Zhou J, Zhou Y, et al. Mycobacterial EST12 activates a RACK1-NLRP3-gasdermin D pyroptosis-IL-1β immune pathway[J]. Sci Adv, 2020, 6(43): eaba4733. doi: 10.1126/sciadv.aba4733

[102] Nayak D, Roth TL, McGavern DB. Microglia development and function[J]. Annu Rev Immunol, 2014, 32: 367-402. doi: 10.1146/annurev-immunol-032713-120240

[103] Wang Y, Ulland TK, Ulrich JD, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques[J]. J Exp Med, 2016, 213(5): 667-675. doi: 10.1084/jem.20151948

[104] Yin H, Song S, Pan X. Correction to: knockdown of miR-155 protects microglia against LPS-induced inflammatory injury via targeting RACK1: a novel research for intracranial infection[J]. J Inflamm, 2018, 15: 6. doi: 10.1186/s12950-018-0183-x

[105] Dan H, Liu S, Liu J, et al. RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF-κB pathway in oral squamous cell carcinoma[J]. Mol Oncol, 2020, 14(4): 795-807. doi: 10.1002/1878-0261.12644

[106] Sun Z, Tang X, Lin F, et al. The WD40 repeat protein WDR26 binds Gβγ and promotes Gβγ-dependent signal transduction and leukocyte migration[J]. J Biol Chem, 2011, 286(51): 43902-43912. doi: 10.1074/jbc.M111.301382

[107] Rigas AC, Ozanne DM, Neal DE, et al. The scaffolding protein RACK1 interacts with androgen receptor and promotes cross-talk through a protein kinase C signaling pathway[J]. J Biol Chem, 2003, 278(46): 46087-46093. doi: 10.1074/jbc.M306219200

[108] Corsini E, Galbiati V, Papale A, et al. Role of androgens in dhea-induced rack1 expression and cytokine modulation in monocytes[J]. Immun Ageing, 2016, 13: 20. doi: 10.1186/s12979-016-0075-y

[109] Corsini E, Lucchi L, Meroni M, et al. In vivo dehydroepiandrosterone restores age-associated defects in the protein kinase C signal transduction pathway and related functional responses[J]. J Immunol, 2002, 168(4): 1753-1758. doi: 10.4049/jimmunol.168.4.1753

[110] Arnold JT. DHEA metabolism in prostate: for better or worse?[J]. Mol Cell Endocrinol, 2009, 301(1-2): 83-88. doi: 10.1016/j.mce.2008.10.019

[111] Pinto A, Malacrida B, Oieni J, et al. DHEA modulates the effect of cortisol on RACK1 expression via interference with the splicing of the glucocorticoid receptor[J]. Br J Pharmacol, 2015, 172(11): 2918-2927. doi: 10.1111/bph.13097

[112] Li X, Li J, Qian J, et al. Loss of ribosomal RACK1 (receptor for activated protein kinase C 1) induced by phosphorylation at T50 alleviates cerebral ischemia-reperfusion injury in rats[J]. Stroke, 2019, 50(1): 162-171. doi: 10.1161/STROKEAHA.118.022404

[113] Zhao Y, Wang Q, Qiu G, et al. RACK1 promotes autophagy by enhancing the atg14L-beclin 1-Vps34-Vps15 complex formation upon phosphorylation by AMPK[J]. Cell Rep, 2015, 13(7): 1407-1417. doi: 10.1016/j.celrep.2015.10.011

[114] Cao J, Zhao M, Liu J, et al. RACK1 promotes self-renewal and chemoresistance of cancer stem cells in human hepatocellular carcinoma through stabilizing nanog[J]. Theranostics, 2019, 9(3): 811-828. doi: 10.7150/thno.29271

[115] Ashique AM, Kharazia V, Yaka R, et al. Localization of the scaffolding protein RACK1 in the developing and adult mouse brain[J]. Brain Res, 2006, 1069(1): 31-38. doi: 10.1016/j.brainres.2005.11.018

[116] Bolger GB, Smoot LHM, van Groen T. Dominant-negative attenuation of cAMP-selective phosphodiesterase PDE4D action affects learning and behavior[J]. Int J Mol Sci, 2020, 21(16): 5704. doi: 10.3390/ijms21165704

[117] Yarwood SJ, Parnell E, Bird RJ. The cyclic AMP phosphodiesterase 4D5 (PDE4D5)/receptor for activated C-kinase 1 (RACK1) signalling complex as a sensor of the extracellular nano-environment[J]. Cell Signall, 2017, 35: 282-289. doi: 10.1016/j.cellsig.2017.01.013