Abstract
A common feature of neurodegenerative disorders, in particular Alzheimer's disease (AD), is a chronic neuroinflammation associated with aberrant neuroplasticity. Development of neuroinflammation affects efficacy of stem and progenitor cells proliferation, differentiation, migration, and integration of newborn cells into neural circuitry. However, precise mechanisms of neurogenesis alterations in neuroinflammation are not clear yet. It is well established that expression of NLRP3 inflammasomes in glial cells marks neuroinflammatory events, but less is known about contribution of NLRP3 to deregulation of neurogenesis within neurogenic niches and whether neural stem cells (NSCs), neural progenitor cells (NPCs) or immature neuroblasts may express inflammasomes in (patho)physiological conditions. Thus, we studied alterations of neurogenesis in rats with the AD model (intra-hippocampal injection of Aβ1-42). We found that in Aβ-affected brain, number of CD133+ cells was elevated after spatial training in the Morris water maze. The number of PSA-NCAM+ neuroblasts diminished by Aβ injection was completely restored by subsequent spatial learning. Spatial training leads to elevated expression of NLRP3 inflammasomes in the SGZ (subgranular zones): CD133+ and PSA-NCAM+ cells started to express NLRP3 in sham-operated, but not AD rats. Taken together, our data suggest that expression of NLRP3 inflammasomes in CD133+ and PSA-NCAM+ cells may contribute to stimulation of adult neurogenesis in physiological conditions, whereas Alzheimer’s type neurodegeneration abolishes stimuli-induced overexpression of NLRP3 within the SGZ neurogenic niche.
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References
Alam A, Hana Z, Jin Z, Suen KC, Ma D (2018) Surgery, neuroinflammation and cognitive impairment. EBioMedicine 37:547–556. https://doi.org/10.1016/j.ebiom.2018.10.021
Apple DM, Fonseca RS, Kokovay E (2017) The role of adult neurogenesis in psychiatric and cognitive disorders. Brain Res 1655:270–276. https://doi.org/10.1016/j.brainres.2016.01.023
Ardura-Fabregat A, Boddeke EWGM, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzériat K, Dansokho C, Dierkes T, Gelders G, Heneka MT, Hoeijmakers L, Hoffmann A, Iaccarino L, Jahnert S, Kuhbandner K, Landreth G, Lonnemann N, Löschmann PA, McManus RM, Paulus A, Reemst K, Sanchez-Caro JM, Tiberi A, Van der Perren A, Vautheny A, Venegas C, Webers A, Weydt P, Wijasa TS, Xiang X, Yang Y (2017) Targeting neuroinflammation to treat Alzheimer’s disease. CNS Drugs 31(12):1057–1082. https://doi.org/10.1007/s40263-017-0483-3
Ashraf A, Mahmoud PA, Reda H, Mansour S, Helal MH, Michel HE, Nasr M (2019) Silymarin and silymarin nanoparticles guard against chronic unpredictable mild stress induced depressive-like behavior in mice: involvement of neurogenesis and NLRP3 inflammasome. J Psychopharmacol 33(5):615–631. https://doi.org/10.1177/0269881119836221
Baglietto-Vargas D, Sánchez-Mejias E, Navarro V, Jimenez S, Trujillo-Estrada L, Gómez-Arboledas A, Sánchez-Mico M, Sánchez-Varo R, Vizuete M, Dávila JC, García-Verdugo JM, Vitorica J, Gutierrez A (2017) Dual roles of Aβ in proliferative processes in an amyloidogenic model of Alzheimer’s disease. Sci Rep 7(1):10085. https://doi.org/10.1038/s41598-017-10353-7
Boese AC, Hamblin MH, Lee J-P (2020) Neural stem cell therapy for neurovascular injury in Alzheimer’s disease. Exp Neurol 324:113112. https://doi.org/10.1016/j.expneurol.2019.113112
Cetin F, Dincer S (2007) The effect of intrahippocampal beta amyloid (1–42) peptide injection on oxidant and antioxidant status in rat brain. Ann N Y Acad Sci 1100(1):510–517. https://doi.org/10.1196/annals.1395.056
Chan EWL, Krishnansamy S, Wong C, Gan SY (2019) The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis. NeuroToxicol 70:91–98. https://doi.org/10.1016/j.neuro.2018.11.001
Chernykh AI, Komleva YuK, Gorina Ya.V., Lopatina OL, Pashchenko S.I., Salmina AB, (2018) Proinflammatory phenotype of perivascular astroglia and CD133+ endothelial cell precursor cells in Alzheimer’s disease modeling in mice. Fundam Clin Med 3:6–15
Chugh D, Nilsson P, Afjei S-A, Bakochi A, Ekdahl CT (2013) Brain inflammation induces post-synaptic changes during early synapse formation in adult-born hippocampal neurons. Exp Neurol 250:176–188. https://doi.org/10.1016/j.expneurol.2013.09.005
Chupel MU, Direito F, Furtado GE, Minuzzi LG, Pedrosa FM, Colado JC, Ferreira JP, Filaire E, Teixeira AM (2017) Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment. Front Physiol 8:377. https://doi.org/10.3389/fphys.2017.00377
Conover JC, Notti RQ (2008) The neural stem cell niche. Cell Tissue Res 331(1):211–224. https://doi.org/10.1007/s00441-007-0503-6
Cope EC, Gould E (2019) Adult neurogenesis, glia, and the extracellular matrix. Cell Stem Cell 24(5):690–705. https://doi.org/10.1016/j.stem.2019.03.023
del Rey A, Balschun D, Wetzel W, Randolf A, Besedovsky HO (2013) A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning. Brain Behav Immun 33:15–23. https://doi.org/10.1016/j.bbi.2013.05.011
Du R-H, Wu F-F, Lu M, Shu X, Ding J-H, Wu G, Hu G (2016) Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression. Redox Biol 9:178–187. https://doi.org/10.1016/j.redox.2016.08.006
Dupret D, Fabre A, Döbrössy MD, Panatier A, Rodríguez JJ, Lamarque S, Lemaire V, Oliet SHR, Piazza P-V, Abrous DN (2007) Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol 5(8):e214. https://doi.org/10.1371/journal.pbio.0050214
Epelbaum S, Youssef I, Lacor PN, Chaurand P, Duplus E, Brugg B, Duyckaerts C, Delatour B (2015) Acute amnestic encephalopathy in amyloid-β oligomer–injected mice is due to their widespread diffusion in vivo. Neurobiol Aging 36(6):2043–2052. https://doi.org/10.1016/j.neurobiolaging.2015.03.005
Epp JR, Chow C, Galea LAM (2013) Hippocampus-dependent learning influences hippocampal neurogenesis. Front Neurosci. https://doi.org/10.3389/fnins.2013.00057
Epp JR, Haack AK, Galea LAM (2011) Activation and survival of immature neurons in the dentate gyrus with spatial memory is dependent on time of exposure to spatial learning and age of cells at examination. Neurobiol Learn Mem 95(3):316–325. https://doi.org/10.1016/j.nlm.2011.01.001
Fan L-W, Pang Y (2017) Dysregulation of neurogenesis by neuroinflammation: key differences in neurodevelopmental and neurological disorders. Neural Regen Res 12(3):366. https://doi.org/10.4103/1673-5374.202926
Fan Z, Lu M, Qiao C, Zhou Y, Ding J-H, Hu G (2016) MicroRNA-7 enhances subventricular zone neurogenesis by inhibiting NLRP3/caspase-1 axis in adult neural stem cells. Mol Neurobiol 53(10):7057–7069. https://doi.org/10.1007/s12035-015-9620-5
Freeman LC, Ting JP-Y (2016) The pathogenic role of the inflammasome in neurodegenerative diseases. J Neurochem 136:29–38. https://doi.org/10.1111/jnc.13217
Goldberg JS, Hirschi KK (2009) Diverse roles of the vasculature within the neural stem cell niche. Regen Med 4(6):879–897. https://doi.org/10.2217/rme.09.61
Goshen I, Kreisel T, Ounallah-Saad H, Renbaum P, Zalzstein Y, Ben-Hur T, Levy-Lahad E, Yirmiya R (2007) A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32(8–10):1106–1115. https://doi.org/10.1016/j.psyneuen.2007.09.004
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999) Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2(3):260–265. https://doi.org/10.1038/6365
Green HF, Nolan YM (2012) Unlocking mechanisms in interleukin-1β-induced changes in hippocampal neurogenesis—a role for GSK-3β and TLX. Transl Psychiatry 2(11):e194–e194. https://doi.org/10.1038/tp.2012.117
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng T-C, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–678. https://doi.org/10.1038/nature11729
Komleva YK, Malinovskaya GorinaLopatina, Volkova, Salmina NAVYOLVVAB (2015) Expression of CD38 and CD157 molecules in olfactory brain bulbs in experimental Alzheimer’s disease. Sib Med Rev 5:44–49
Komleva YK, Lopatina OL, YaV G, Chernykh AI, Shuvaev AN, Salmina AB (2018) Early changes in hyppocampal neurogenesis induced by soluble Ab1-42 oligomers. Biomed Khim 64(4):326–333
Lee H-M, Kim J-J, Kim HJ, Shong M, Ku BJ, Jo E-K (2013) Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62(1):194–204. https://doi.org/10.2337/db12-0420
Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH (2013) Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain 136(5):1383–1398. https://doi.org/10.1093/brain/awt062
Leuner B, Gould E (2010) Structural plasticity and hippocampal function. Annu Rev Psychol 61(1):111–140. https://doi.org/10.1146/annurev.psych.093008.100359
Li T, Wang L, Hu Q, Liu S, Bai X, Xie Y, Zhang T, Bo S, Gao X, Wu S, Li G, Wang Z (2017) Neuroprotective roles of l-cysteine in attenuating early brain injury and improving synaptic density via the CBS/H2S pathway following subarachnoid hemorrhage in rats. Front Neurol 8:176. https://doi.org/10.3389/fneur.2017.00176
Ly PTT, Cai F, Song W (2011) Detection of neuritic plaques in Alzheimer’s disease mouse model. JoVE 53:2831. https://doi.org/10.3791/2831
Ma L, Li X, Zhang S, Yang F, Zhu G, Yuan X, Jiang W (2014) Interleukin-1 beta guides the migration of cortical neurons. J Neuroinflam 11(1):114. https://doi.org/10.1186/1742-2094-11-114
Marsland AL, Gianaros PJ, Kuan DC-H, Sheu LK, Krajina K, Manuck SB (2015) Brain morphology links systemic inflammation to cognitive function in midlife adults. Brain Behav Immun 48:195–204. https://doi.org/10.1016/j.bbi.2015.03.015
Murray HC, Low VF, Swanson MEV, Dieriks BV, Turner C, Faull RLM, Curtis MA (2016) Distribution of PSA-NCAM in normal, Alzheimer’s and Parkinson’s disease human brain. Neuroscience 330:359–375. https://doi.org/10.1016/j.neuroscience.2016.06.003
Nakanishi A, Kaneko N, Takeda H, Sawasaki T, Morikawa S, Zhou W, Kurata M, Yamamoto T, Akbar SMF, Zako T, Masumoto J (2018) Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system. Inflamm Regen 38(1):27. https://doi.org/10.1186/s41232-018-0085-6
Nazem A, Sankowski R, Bacher M, Al-Abed Y (2015) Rodent models of neuroinflammation for Alzheimer’s disease. J Neuroinflammation 12(1):74. https://doi.org/10.1186/s12974-015-0291-y
Okano H, Sawamoto K (2008) Neural stem cells: involvement in adult neurogenesis and CNS repair. Philos Trans R Soc B 363(1500):2111–2122. https://doi.org/10.1098/rstb.2008.2264
Pan H, Wang D, Zhang X, Zhou D, Zhang H, Qian Q, He X, Liu Z, Liu Y, Zheng T, Zhang L, Wang M, Sun B (2016) Amyloid β is not the major factor accounting for impaired adult hippocampal neurogenesis in mice overexpressing amyloid precursor protein. Stem Cell Rep 7(4):707–718. https://doi.org/10.1016/j.stemcr.2016.08.019
Park S-Y, Kang M-J, Han J-S (2018) Interleukin-1 beta promotes neuronal differentiation through the Wnt5a/RhoA/JNK pathway in cortical neural precursor cells. Mol Brain 11(1):39. https://doi.org/10.1186/s13041-018-0383-6
Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates, compact, 2nd edn. Academic Press , Boston
Sakurai K, Osumi N (2008) The neurogenesis-controlling factor, Pax 6, inhibits proliferation and promotes maturation in murine astrocytes. J Neurosci 28(18):4604–4612. https://doi.org/10.1523/JNEUROSCI.5074-07.2008
Sansom SN, Griffiths DS, Faedo A, Kleinjan D-J, Ruan Y, Smith J, van Heyningen V, Rubenstein JL, Livesey FJ (2009) The level of the transcription factor Pax6 Is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genet 5(6):e1000511. https://doi.org/10.1371/journal.pgen.1000511
Sartori AC, Vance DE, Slater LZ, Crowe M (2012) The impact of inflammation on cognitive function in older adults: implications for healthcare practice and research. J Neurosci Nurs 44(4):206–217. https://doi.org/10.1097/JNN.0b013e3182527690
Sengupta P (2013) The laboratory rat: relating its age with human’s. Int J Prevent Med 4(6):624–630
Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C (2015) NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. https://doi.org/10.3389/fphar.2015.00262
Sloan RP, Shapiro PA, McKinley PS, Bartels M, Shimbo D, Lauriola V, Karmally W, Pavlicova M, Choi CJ, Choo T, Scodes JM, Flood P, Tracey KJ (2018) Aerobic exercise training and inducible inflammation: results of a randomized controlled trial in healthy. J Am Heart Assoc Young Adults. https://doi.org/10.1161/JAHA.118.010201
Song L, Pei L, Yao S, Wu Y, Shang Y (2017) NLRP3 inflammasome in neurological diseases, from functions to therapies. Front Cell Neurosci. https://doi.org/10.3389/fncel.2017.00063
Than-Trong E, Ortica-Gatti S, Mella S, Nepal C, Alunni A, Bally-Cuif L (2018) Neural stem cell quiescence and stemness are molecularly distinct outputs of the Notch3 signalling cascade in the vertebrate adult brain. Development. https://doi.org/10.1242/dev.161034
Thawkar BS, Kaur G (2019) Inhibitors of NF-κB and P2X7/NLRP3/caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease. J Neuroimmunol 326:62–74. https://doi.org/10.1016/j.jneuroim.2018.11.010
Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1(2):848–858. https://doi.org/10.1038/nprot.2006.116
Wang H-M, Zhang T, Huang J-K, Xiang J-Y, Chen J, Fu J-L, Zhao Y-W (2017) Edaravone attenuates the proinflammatory response in amyloid-β-treated microglia by Inhibiting NLRP3 inflammasome-mediated IL-1β secretion. Cell Physiol Biochem 43(3):1113–1125. https://doi.org/10.1159/000481753
Wen J, Hu Q, Li M, Wang S, Zhang L, Chen Y, Li L (2008) Pax6 directly modulate Sox2 expression in the neural progenitor cells. NeuroReport 19(4):413–417
Wu MD, Montgomery SL, Rivera-Escalera F, Olschowka JA, O’Banion MK (2013) Sustained IL-1β expression impairs adult hippocampal neurogenesis independent of IL-1 signaling in nestin+ neural precursor cells. Brain Behav Immun 32:9–18. https://doi.org/10.1016/j.bbi.2013.03.003
Yeung ST, Martinez-Coria H, Ager RR, Rodriguez-Ortiz CJ, Baglietto-Vargas D, LaFerla FM (2015) Repeated cognitive stimulation alleviates memory impairments in an Alzheimer’s disease mouse model. Brain Res Bull 117:10–15. https://doi.org/10.1016/j.brainresbull.2015.07.001
Yin J, Zhao F, Chojnacki JE, Fulp J, Klein WL, Zhang S, Zhu X (2018) NLRP3 inflammasome inhibitor ameliorates amyloid pathology in a mouse model of Alzheimer’s disease. Mol Neurobiol 55(3):1977–1987. https://doi.org/10.1007/s12035-017-0467-9
Ying Z, Gonzalez-Martinez J, Tilelli C, Bingaman W, Najm I (2005) Expression of neural stem cell surface marker CD133 in balloon cells of human focal cortical dysplasia. Epilepsia 46(11):1716–1723. https://doi.org/10.1111/j.1528-1167.2005.00276.x
Zeng J, Jiang X, Hu X-F, Ma R-H, Chai G-S, Sun D-S, Xu Z-P, Li L, Bao J, Feng Q, Hu Y, Chu J, Chai D, Hong X-Y, Wang J-Z, Liu G-P (2016) Spatial training promotes short-term survival and neuron-like differentiation of newborn cells in Aβ 1–42 -injected rats. Neurobiol Aging 45:64–75. https://doi.org/10.1016/j.neurobiolaging.2016.05.005
Zhang J, Jiao J (2015) Molecular biomarkers for embryonic and adult neural stem cell and neurogenesis. Biomed Res Int 2015:1–14. https://doi.org/10.1155/2015/727542
Acknowledgements
We thank Assoc. Prof. Oksana Gavrilyuk and Assist. Prof. Ekaterina Andryushkina (International Programs Center, KrasSMU) for their assistance with proofreading. This work was supported by a grant from the President of the Russian Federation for State support of the leading scientific schools of the Russian Federation 6240.2018.7 and 2547.2020.7.
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YK, AS designed the study; YK, OL, YG, AC, LT, EV, EKh, EZh, LS, NM performed the experiments; YK and AS wrote the manuscript. All authors have approved the final version of the paper.
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Komleva, Y.K., Lopatina, O.L., Gorina, Y.V. et al. Expression of NLRP3 Inflammasomes in Neurogenic Niche Contributes to the Effect of Spatial Learning in Physiological Conditions but Not in Alzheimer’s Type Neurodegeneration. Cell Mol Neurobiol 42, 1355–1371 (2022). https://doi.org/10.1007/s10571-020-01021-y
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DOI: https://doi.org/10.1007/s10571-020-01021-y