Research Advances in the Association Between Alzheimer's Disease and Double-Stranded RNA-Dependent Protein Kinase

Yi GONG; Xingyang XIAO; Yousheng HU; Yiwei XIE; Zhihui WU

doi:10.3881/j.issn.1000-503X.15792

PDF(6912 KB)

Acta Academiae Medicinae Sinicae ›› 2024, Vol. 46 ›› Issue (3) : 425-434. DOI: 10.3881/j.issn.1000-503X.15792

Review Articles

Research Advances in the Association Between Alzheimer's Disease and Double-Stranded RNA-Dependent Protein Kinase

Yi GONG ¹ ,
Xingyang XIAO ¹ ,
Yousheng HU ¹^,² ,
Yiwei XIE ³ ,
Zhihui WU ³

Author information +

History +

Abstract

Alzheimer's disease(AD)is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase(PKR)is an interferon-induced protein kinase involved in innate immunity.in the occurrence and development of AD,PKR is upregulated and continuously activated.On the one hand,the activation of PKR triggers an integrated stress response in brain cells.On the other hand,it indirectly upregulates the expression ofβ-site amyloid precursor protein cleaving enzyme 1 and facilitates the accumulation of amyloid-βprotein(Aβ),which could activate PKR activator to further activate PKR,thus forming a sustained accumulation cycle of Aβ.in addition,PKR can promote Tau phosphorylation,thereby reducing microtubule stability in nerve cells.Inflammation in brain tissue,neurotoxicity resulted from Aβaccumulation,and disruption of microtubule stability led to the progression of AD and the declines of memory and cognitive function.Therefore,PKR is a key molecule in the development and progression of AD.Effective PKR detection can aid in the diagnosis and prediction of AD progression and provide opportunities for clinical treatment.the inhibitors targeting PKR are expected to control the activity of PKR,thereby controlling the progression of AD.Therefore,PKR could be a target for the development of therapeutic drugs for AD。

Key words

Alzheimer's disease / double-stranded RNA-dependent protein kinase / amyloid-beta / Tau

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

Yi GONG , Xingyang XIAO , Yousheng HU , et al . Research Advances in the Association Between Alzheimer's Disease and Double-Stranded RNA-Dependent Protein Kinase[J]. Acta Academiae Medicinae Sinicae. 2024, 46(3): 425-434 https://doi.org/10.3881/j.issn.1000-503X.15792

References

List( Publishing order | Descend order by publishing year | Descend order by cited within ) Chart analysis

[1]

Petersen

, Lopez

, Armstrong

, et al. Practice guideline update summary:mild cognitive impairment:report of the Guideline Development,Dissemination,and Implementation Subcommittee of the American Academy of Neurology[J]. Neurology, 2018, 90(3):126-135.DOI:10.1212/wnl.0000000000004826.

Cited in this article [1]

[2]	Alzheimer's Association. 2023 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2023, 19(4):1598-1695.DOI:10.1002/alz.13016. Cited in this article [1]

[3]	Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention,intervention,and care:2020 report of the Lancet Commission[J]. Lancet (London,England), 2020, 396(10248):413-446.DOI:10.1016/s0140-6736(20)30367-6. Cited in this article [2]

[4]	Kapasi A, Leurgans SE, Arvanitakis Z, et al. Abeta (Amyloid Beta) and Tau tangle pathology modifies the association between small vessel disease and cortical microinfarcts[J]. Stroke, 2021, 52(3):1012-1021.DOI:10.1161/STROKEAHA.120.031073. Cited in this article [2]

[5]	Behl T, Kaur I, Fratila O, et al. Exploring the potential of therapeutic agents targeted towards mitigating the events associated with Amyloid-β cascade in Alzheimer's disease[J]. Int J Mol Sci, 2020, 21(20):7473.DOI:10.3390/ijms21207443. Cited in this article [2]

[6]	Cline EN, Bicca MA, Viola KL, et al. The amyloid-β oligomer hypothesis:beginning of the third decade[J]. J Alzheimers Dis, 2018, 64(s1):S567-S610.DOI:10.3233/jad-179941. Cited in this article [2]

[7]	Hamano T, Enomoto S, Shirafuji N, et al. Autophagy and Tau protein[J]. Int J Mol Sci, 2021, 22(14):7574.DOI:10.3390/ijms22147475. Cited in this article [2]

[8]	Otero-Garcia M, Mahajani SU, Wakhloo D, et al. Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease[J]. Neuron, 2022, 110(18):2929-2948.e8.DOI:10.1016/j.neuron.2022.06.021. Cited in this article [2]

[9]	Huang F, Wang M, Liu R, et al. CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease[J]. Alzheimers Dement, 2019, 15(2):217-231.DOI:10.1016/j.jalz.2018.08.013. Cited in this article [2]

[10]	Wang Q, Xie C. Microglia activation linking amyloid-β drive tau spatial propagation in Alzheimer's disease[J]. Front Neurosci, 2022, 16:951128.DOI:10.3389/fnins.2022.951128. Cited in this article [2]

[11]	Ittner A, Ittner LM. Dendritic Tau in Alzheimer's disease[J]. Neuron, 2018, 99(1):13-27.DOI:10.1016/j.neuron.2018.06.003. Cited in this article [3]

[12]	Chukwurah E, Farabaugh KT, Guan BJ, et al. A tale of two proteins:PACT and PKR and their roles in inflammation[J]. FEBS J, 2021, 288(22):6365-6391.DOI:10.1111/febs.15691. Cited in this article [3]

[13]	Lee S, Jee HY, Lee YG, et al. PKR-Mediated phosphorylation of eIF2a and CHK1 is associated with doxorubicin-mediated apoptosis in hCC1143 triple-negative breast cancer cells[J]. Int J Mol Sci, 2022, 23(24):15872.DOI:10.3390/ijms232415872. Cited in this article [3]

[14]

Zhang

, Zhang

, Li

, et al. Activation of double-stranded RNA-activated protein kinase in the dorsal root ganglia and spinal dorsal horn regulates neuropathic pain following peripheral nerve injury in rats[J]. Neurotherapeutics, 2022, 19(4):1381-1400.DOI:10.1007/s13311-022-01255-2.

Cited in this article [3]

[15]	Lu W, Tang S, Li A, et al. The role of PKC/PKR in aging,Alzheimer's disease,and perioperative neurocognitive disorders[J]. Front Aging Neurosci, 2022, 14:973068.DOI:10.3389/fnagi.2022.973068. Cited in this article [6]

[16]	Upadhyay A, Chhangani D, Rao NR, et al. Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity[J]. Mol Neurodegener, 2023, 18(1):61.DOI:10.1186/s13024-023-00654-z. Cited in this article [4]

[17]	Futamura A, Hieda S, Mori Y, et al. Toxic Amyloid-β42 conformer may accelerate the onset of Alzheimer's disease in the preclinical stage[J]. J Alzheimers Dis, 2021, 80(2):639-646.DOI:10.3233/jad-201407. Cited in this article [4]

[18]	Tible M, Mouton Liger F, Schmitt J, et al. PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions[J]. Aging cell, 2019, 18(3):e12887.DOI:10.1111/acel.12887. Cited in this article [9]

[19]	Hasan U, Singh SK. The Astrocyte-Neuron Interface:An overview on molecular and cellular dynamics controlling formation and maintenance of the tripartite synapse[J]. Methods Mol Biol, 2019, 1938:3-18.DOI:10.1007/978-1-4939-9068-9_1. Cited in this article [1]

[20]	Ikegami A, Haruwaka K, Wake H. Microglia:lifelong modulator of neural circuits[J]. Neuropathology, 2019, 39(3):173-180.DOI:10.1111/neup.12560. Cited in this article [1]

[21]	Konishi H, Kiyama H, Ueno M. Dual functions of microglia in the formation and refinement of neural circuits during development[J]. Int J Dev Neurosci, 2019, 77:18-25.DOI:10.1016/j.ijdevneu.2018.09.009. Cited in this article [1]

[22]	Olsen M, Aguilar X, Sehlin D, et al. Astroglial responses to amyloid-beta progression in a mouse model of Alzheimer's disease[J]. Mol Imaging Biol, 2018, 20(4):605-614.DOI:10.1007/s11307-017-1153-z. Cited in this article [1]

[23]	Litwiniuk A, Juszczak GR, Stankiewicz AM, et al. The role of glial autophagy in Alzheimer's disease[J]. Mol Psychiatry, 2023, 28(11):4528-4539.DOI:10.1038/s41380-023-02242-5. Cited in this article [1]

[24]	Liu Q, Contreras A, Afaq MS, et al. Intensity-dependent gamma electrical stimulation regulates microglial activation,reduces beta-amyloid load,and facilitates memory in a mouse model of Alzheimer's disease[J]. Cell Biosci, 2023, 13(1):138.DOI:10.1186/s13578-023-01085-5. Cited in this article [3]

[25]	Zhang Y, Jia J. Betaine Mitigates Amyloid-β-Associated neuroinflammation by suppressing the NLRP3 and NF-κB signaling pathways in microglial cells[J]. J Alzheimers Dis, 2023, 94(s1):S9-S19.DOI:10.3233/jad-230064. Cited in this article [3]

[26]	Liu W, Chen S, Rao X, et al. The inflammatory gene PYCARD of the entorhinal cortex as an early diagnostic target for Alzheimer's disease[J]. Biomedicines, 2023, 11(1):194.DOI:10.3390/biomedicines11010194. Cited in this article [3]

[27]	Španić E, Langer Horvat L, Ilić K, et al. NLRP1 inflammasome activation in the hippocampal formation in Alzheimer's disease:correlation with neuropathological changes and unbiasedly estimated neuronal loss[J]. Cells, 2022,11(14):2223.DOI:10.3390/cells11142223. Cited in this article [3]

[28]	Bouteiller JC, Mergenthal AR, Hu E, et al. Pathogenic processes underlying Alzheimer's disease:modeling the effects of Amyloid beta on synaptic transmission[J]. Annu Int Conf IEEE Eng Med Biol Soc, 2019, 2019:1956-1959.DOI:10.1109/embc.2019.8857871. Cited in this article [4]

[29]	Castellani RJ, PLASCENCIA-VILLA G, Perry G. The amyloid cascade and Alzheimer's disease therapeutics:theory versus observation[J]. Lab Invest, 2019, 99(7):958-970.DOI:10.1038/s41374-019-0231-z. Cited in this article [4]

[30]	Ratan Y, Rajput A, Maleysm S, et al. An insight into cellular and molecular mechanisms underlying the pathogenesis of neurodegeneration in Alzheimer's disease[J]. Biomedicines, 2023, 11(5):1398.DOI:10.3390/biomedicines11051398. Cited in this article [3]

[31]	Bond S, Lopez-Lloreda C, Gannon PJ, et al. The integrated stress response and phosphorylated eukaryotic initiation factor 2α in neurodegeneration[J]. J Neuropathol Exp Neurol, 2020, 79(2):123-143.DOI:10.1093/jnen/nlz129. Cited in this article [4]

[32]	Qiao H, Jiang T, Mu P, et al. Cell fate determined by the activation balance between PKR and SPHK1[J]. Cell Death Differ, 2021, 28(1):401-418.DOI:10.1038/s41418-020-00608-8. Cited in this article [2]

[33]	Hugon J, Paquet C. The PKR/P38/RIPK1 signaling pathway as a therapeutic target in Alzheimer's disease[J]. Int J Mol Sci, 2021, 22(6):3136.DOI:10.3390/ijms22063136. Cited in this article [3]

[34]	Chiarini A, Armato U, Hu P, et al. Danger-Sensing/Patten recognition receptors and neuroinflammation in Alzheimer's disease[J]. Int J Mol Sci, 2020, 21(23):9036.DOI:10.3390/ijms21239036. Cited in this article [2]

[35]	刘松杨, 程楠, 徐陈陈, 等. 肝豆汤改良方调控PKR/eIF2α通路改善Wilson病模型TX小鼠突触功能障碍的机制研究[J]. 安徽中医药大学学报, 2021, 40(6):75-81.DOI:10.3969/j.issn.2095-7246.2021.06.017. Cited in this article [3]

[36]	Zhang J S, Zhou SF, Wang Q, et al. Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2α pathway in Alzheimer's disease[J]. Neuroscience, 2016, 325:1-9.DOI:10.1016/j.neuroscience.2016.03.024. Cited in this article [3]

[37]	Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells[J]. Front Aging Neurosci, 2016, 8:160.DOI:10.3389/fnagi.2016.00160. Cited in this article [1]

[38]	Khandelwal PJ, Herman AM, Moussa CE. Inflammation in the early stages of neurodegenerative pathology[J]. J Neuroimmunol, 2011, 238(1-2):1-11.DOI:10.1016/j.jneuroim.2011.07.002. Cited in this article [1]

[39]	Deng Z, Dong Y, Zhou X, et al. Pharmacological modulation of autophagy for Alzheimer's disease therapy:opportunities and obstacles[J]. Acta Pharm Sin B, 2022, 12(4):1688-1706.DOI:10.1016/j.apsb.2021.12.009. Cited in this article [1]

[40]	Suresh S, Larson J, Jenrow KA. Chronic neuroinflammation impairs waste clearance in the rat brain[J]. Front Neuroanat, 2022, 16:1013808.DOI:10.3389/fnana.2022.1013808. Cited in this article [1]

[41]	Doroszkiewicz J, Mroczko P, Kulczyńska-Przybik A. Inflammation in the CNS:understanding various aspects of the pathogenesis of Alzheimer's disease[J]. Curr Alzheimer Res, 2022, 19(1):16-31.DOI:10.2174/1567205018666211202143935. Cited in this article [1]

[42]	Lopez-Grancha M, Bernardelli P, Moindrot N, et al. A novel selective PKR inhibitor restores cognitive deficits and neurodegeneration in Alzheimer disease experimental models[J]. J Pharmacol Exp Ther, 2021, 378(3):262-275.DOI:10.1124/jpet.121.000590. Cited in this article [3]

[43]	邓嘉强, 井秀娜, 林淡钰, 等. 利福平通过抑制蛋白激酶R活化调节鱼藤酮诱导的小胶质细胞炎症而发挥神经保护作用[J]. 岭南急诊医学杂志, 2021, 26(2):121-124.DOI:10.3969/j.issn.1671-301X.2021.02.004. Cited in this article [2]

[44]	Rice HC, de Malmazet D, Schreurs A, et al. Secreted amyloid-β precursor protein functions as a GABA(B)R1a ligand to modulate synaptic transmission[J]. Science, 2019, 363(6423):eaao4827.DOI:10.1126/science.aao4827. Cited in this article [1]

[45]	Mañucat-Tan NB, Saadipour K, Wang YJ, et al. Cellular trafficking of amyloid precursor protein in amyloidogenesis physiological and pathological significance[J]. Mol Neurobiol, 2019, 56(2):812-830.DOI:10.1007/s12035-018-1106-9. Cited in this article [1]

[46]	Ma C, Hong F, Yang S. Amyloidosis in Alzheimer's disease:pathogeny,etiology,and related therapeutic directions[J]. Molecules, 2022, 27(4):1210.DOI:10.3390/molecules27041210. Cited in this article [2]

[47]	Glenner GG, Wong CW. Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein[J]. Biochem Biophys Res Commun, 1984, 120(3):885-890.DOI:10.1016/s0006-291x(84)80190-4. Cited in this article [1]

[48]	Yakupova EI, Bobyleva LG, Shumeyko SA, et al. Amyloids:the history of toxicity and functionality[J]. Biology, 2021, 10(5):394.DOI:10.3390/biology10050394. Cited in this article [1]

[49]	Guix FX, Sartório CL, Ill-Raga G. BACE1 translation:at the crossroads between Alzheimer's disease neurodegeneration and memory consolidation[J]. J Alzheimers Dis Rep, 2019, 3(1):113-148.DOI:10.3233/adr-180089. Cited in this article [1]

[50]	Syeda T, Cannon JR. Environmental exposures and the etiopathogenesis of Alzheimer's disease:the potential role of BACE1 as a critical neurotoxic target[J]. J Biochem Mol Toxicol, 2021, 35(4):e22694.DOI:10.1002/jbt.22694. Cited in this article [1]

[51]	Volloch V, Rits-Volloch S. The amyloid cascade hypothesis 2.0 for Alzheimer's disease and aging-associated cognitive decline:from molecular basis to effective therapy[J]. Int J Mol Sci, 2023, 24(15):12246.DOI:10.3390/ijms241512246. Cited in this article [1]

[52]	Gourmaud S, Mouton-Liger F, Abadie C, et al. Dual kinase inhibition affords extended in vitro neuroprotection in Amyloid-β toxicity[J]. J Alzheimers Dis, 2016, 54(4):1659-1670.DOI:10.3233/jad-160509. Cited in this article [2]

[53]	Lourenco MV, Clarke JR, Frozza RL, et al. TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys[J]. Cell Metab, 2013, 18(6):831-843.DOI:10.1016/j.cmet.2013.11.002. Cited in this article [1]

[54]	Chan AWS, Cho IK, Li CX, et al. Cerebral Aβ deposition in an Aβ-precursor protein-transgenic rhesus monkey[J]. Aging Brain, 2022, 2:100044.DOI:10.1016/j.nbas.2022.100044. Cited in this article [1]

[55]	Mouton-Liger F, Rebillat AS, Gourmaud S, et al. PKR downregulation prevents neurodegeneration and β-amyloid production in a thiamine-deficient model[J]. Cell Death Dis, 2015, 6(1):e1594.DOI:10.1038/cddis.2014.552. Cited in this article [1]

[56]	Carret-Rebillat AS, Pace C, GourmauDS, et al. Neuroinflammation and Aβ accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation[J]. Sci Rep, 2015, 5:8489.DOI:10.1038/srep08489. Cited in this article [1]

[57]	Paquet C, Mouton-Liger F, Meurs EF, et al. The PKR activator PACT is induced by Aβ:involvement in Alzheimer's disease[J]. Brain Pathol, 2012, 22(2):219-229.DOI:10.1111/j.1750-3639.2011.00520.x. Cited in this article [1]

[58]	Chen Y, Yu Y. Tau and neuroinflammation in Alzheimer's disease:interplay mechanisms and clinical translation[J]. J Neuroinflammation, 2023, 20(1):165.DOI:10.1186/s12974-023-02853-3. Cited in this article [1]

[59]	el Mammeri N, Duan P, Dregni AJ, et al. Amyloid fibril structures of tau:conformational plasticity of the second microtubule-binding repeat[J]. Sci Adv, 2023, 9(28):eadh4731.DOI:10.1126/sciadv.adh4731. Cited in this article [1]

[60]	Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease[J]. Nat Rev Neurol, 2018, 14(7):399-415.DOI:10.1038/s41582-018-0013-z. Cited in this article [1]

[61]	Dejanovic B, Huntley MA, de Mazière A, et al. Changes in the synaptic proteome in tauopathy and rescue of Tau-induced synapse loss by c1q antibodies[J]. Neuron, 2018, 100(6):1322-1336.e7.DOI:10.1016/j.neuron.2018.10.014. Cited in this article [1]

[62]	Reimer L, Betzer C, Kofoed RH, et al. PKR kinase directly regulates tau expression and Alzheimer's disease-related tau phosphorylation[J]. Brain Pathol, 2021, 31(1):103-119.DOI:10.1111/bpa.12883. Cited in this article [5]

[63]	Dubbelman MA, Mimmack KJ, Sprague EH, et al. Regional cerebral tau predicts decline in everyday functioning across the Alzheimer's disease spectrum[J]. Alzheimers Res Ther, 2023, 15(1):120.DOI:10.1186/s13195-023-01267-w. Cited in this article [2]

[64]	Moradi Majd R, Mayeli M, Rahmani F. Pathogenesis and promising therapeutics of Alzheimer disease through eIF2α pathway and correspondent kinases[J]. Metab Brain Dis, 2020, 35(8):1241-1250.DOI:10.1007/s11011-020-00600-8. Cited in this article [1]

[65]	Drummond E, Pires G, Macmurray C, et al. Phosphorylated tau interactome in the human Alzheimer's disease brain[J]. Brain, 2020, 143(9):2803-2817.DOI:10.1093/brain/awaa223. Cited in this article [1]

[66]	Turab Naqvi AA, Hasan GM, Hassan MI. Targeting Tau hyperphosphorylation via kinase inhibition:strategy to address Alzheimer's disease[J]. Curr Top Med Chem, 2020, 20(12):1059-1073.DOI:10.2174/1568026620666200106125910. Cited in this article [1]

[67]	Amin J, Paquet C, Baker A, et al. Effect of amyloid-β (Aβ) immunization on hyperphosphorylated tau:a potential role for glycogen synthase kinase (GSK)-3β[J]. Neuropathol Appl Neurobiol, 2015, 41(4):445-457.DOI:10.1111/nan.12205. Cited in this article [1]

[68]	生晓娜, 李潇潇, 张晓炜, 等. 阿尔茨海默病患者淋巴细胞中双链RNA-依赖的蛋白激酶水平与认知障碍的相关性[J]. 中风与神经疾病杂志, 2017, 34(8):692-695.DOI:10.19845/j.cnki.zfysjjbzz.2017.08.005. Cited in this article [2]

[69]	Monllor P, Giraldo E, Badia MC, et al. Serum levels of clusterin,PKR,and RAGE correlate with amyloid burden in Alzheimer's disease[J]. J Alzheimers Dis, 2021, 80(3):1067-1077.DOI:10.3233/jad-201443. Cited in this article [2]

[70]	Dumurgier J, Mouton-Liger F, Lapalus P, et al. Cerebrospinal fluid PKR level predicts cognitive decline in Alzheimer's disease[J]. PLoS One, 2013, 8(1):e53587.DOI:10.1371/journal.pone.0053587. Cited in this article [1]

[71]	Paquet C, Dumurgier J, Hugon J. Pro-apoptotic kinase levels in cerebrospinal fluid as potential future biomarkers in Alzheimer's disease[J]. Front Neurol, 2015, 6:168.DOI:10.3389/fneur.2015.00168. Cited in this article [1]

[72]

Zeng

, Wang

, Zhou

, et al. NMDA receptor antagonists engender neuroprotection against gp120-induced cognitive dysfunction in rats through modulation of PKR activation,oxidative stress,ER stress and IRE1α signal pathway[J]. Eur J Neurosci, 2022, 56(2):3806-3824.DOI:10.1111/ejn.15688.

Cited in this article [1]

[73]	Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer's disease[J]. N Engl J Med, 2019, 380(15):1408-1420.DOI:10.1056/NEJMoa1812840. Cited in this article [2]

[74]	Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer's disease[J]. N Engl J Med, 2018, 378(18):1691-1703.DOI:10.1056/NEJMoa1706441. Cited in this article [1]