Journal Home > Online First

Alzheimer's disease (AD), a prevalent form of dementia in the elderly, is characterized by marked neurodegeneration and cognitive decline. Central to its pathology are Amyloid-beta plaques, neurofibrillary tangles, and neuroinflammation. This review delves into the pivotal role of microglia, the primary immune cells in the central nervous system, in AD's progression. We highlight recent discoveries revealing how abnormal microglial activity, influenced by mitochondrial dysfunction, contributes to AD development. Special attention is given to the bidirectional relationship between microglia and mitochondria, including the impact of metabolic disturbances and energy dysregulation on microglial function. Further, we explore the mechanisms underlying microglial activation and its consequences on neuronal health, including the interplay between inflammatory pathways and mitochondrial dynamics. Our comprehensive analysis underscores the significance of mitochondrial homeostasis in microglial functionality and its implications for AD progression, offering insights into potential therapeutic avenues targeting microglial mitochondria in AD.


menu
Abstract
Full text
Outline
About this article

The interaction between microglial dysfunction and mitochondrial impairment in Alzheimer’s disease

Show Author's information Qiudan Luo1Ji Heon Noh2Jian Sima1( )
Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Department of Biochemistry, Chungnam National University, Daejeon 34134, Korea

Abstract

Alzheimer's disease (AD), a prevalent form of dementia in the elderly, is characterized by marked neurodegeneration and cognitive decline. Central to its pathology are Amyloid-beta plaques, neurofibrillary tangles, and neuroinflammation. This review delves into the pivotal role of microglia, the primary immune cells in the central nervous system, in AD's progression. We highlight recent discoveries revealing how abnormal microglial activity, influenced by mitochondrial dysfunction, contributes to AD development. Special attention is given to the bidirectional relationship between microglia and mitochondria, including the impact of metabolic disturbances and energy dysregulation on microglial function. Further, we explore the mechanisms underlying microglial activation and its consequences on neuronal health, including the interplay between inflammatory pathways and mitochondrial dynamics. Our comprehensive analysis underscores the significance of mitochondrial homeostasis in microglial functionality and its implications for AD progression, offering insights into potential therapeutic avenues targeting microglial mitochondria in AD.

Keywords: microglia, mitochondria, Alzheimer's disease (AD), neuroinflammation

References(125)

[1]
2023 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 2023, 19(4): 1598–1695. https://doi.org/10.1002/alz.13016
DOI
[2]

Ginhoux, F., Garel, S. The mysterious origins of microglia. Nature Neuroscience, 2018, 21(7): 897–899. https://doi.org/10.1038/s41593-018-0176-3

[3]

Alliot, F., Godin, I., Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Developmental Brain Research, 1999, 117(2): 145–152. https://doi.org/10.1016/s0165-3806(99)00113-3

[4]

Cuadros, M. A., Martin, C., Coltey, P, Almendros, A., Navascués, J. First appearance, distribution, and origin of macrophages in the early development of the avian central nervous system. The Journal of Comparative Neurology, 1993, 330(1): 113–129. https://doi.org/10.1002/cne.903300110

[5]

Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., Wieghofer, P., Heinrich, A., Riemke, P., Hölscher, C. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nature Neuroscience, 2013, 16(3): 273–280. https://doi.org/10.1038/nn.3318

[6]

Borst, K., Dumas, A. A., Prinz, M. Microglia: Immune and non-immune functions. Immunity, 2021, 54(10): 2194–2208. https://doi.org/10.1016/j.immuni.2021.09.014

[7]

Colonna, M., Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annual Review of Immunology, 2017, 35: 441–468. https://doi.org/10.1146/annurev-immunol-051116-052358

[8]

Bertani, F. R., Mozetic, P., Fioramonti, M., Iuliani, M., Ribelli, G., Pantano, F., Santini, D., Tonini, G., Trombetta, M., Businaro, L. et al. Classification of M1/M2-polarized human macrophages by label-free hyperspectral reflectance confocal microscopy and multivariate analysis. Scientific Reports, 2017, 7: 8965. https://doi.org/10.1038/s41598-017-08121-8

[9]

Zhang, W. B., Baban, B., Rojas, M., Tofigh, S., Virmani, S. K., Patel, C., Behzadian, M. A., Romero, M. J., Caldwell, R. W., Caldwell, R. B. Arginase activity mediates retinal inflammation in endotoxin-induced uveitis. The American Journal of Pathology, 2009, 175(2): 891–902. https://doi.org/10.2353/ajpath.2009.081115

[10]

Wang, W. Y., Tan, M. S., Yu, J. T., Tan, L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med, 2015, 3(10): 136. https://doi.org/10.3978/j.issn.2305-5839.2015.03.49

[11]

Bivona, G., Iemmolo, M., Agnello, L., Lo Sasso, B., Gambino, C. M., Giglio, R. V., Scazzone, C., Ghersi, G., Ciaccio, M. Microglial activation and priming in alzheimer’s disease: State of the art and future perspectives. International Journal of Molecular Sciences, 2023, 24(1): 884. https://doi.org/10.3390/ijms24010884

[12]

Hickman, S. E., Allison, E. K., El Khoury, J. Microglial dysfunction and defective β-amyloid clearance pathways in aging alzheimer’s disease mice. The Journal of Neuroscience, 2008, 28(33): 8354–8360. https://doi.org/10.1523/JNEUROSCI.0616-08.2008

[13]

Condello, C., Yuan, P., Schain, A., Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nature Communications, 2015, 6: 6176. https://doi.org/10.1038/ncomms7176

[14]

Li, Y., Xia, X. H., Wang, Y., Zheng, J. C. Mitochondrial dysfunction in microglia: A novel perspective for pathogenesis of Alzheimer’s disease. Journal of Neuroinflammation, 2022, 19(1): 19. https://doi.org/10.1186/s12974-022-02613-9

[15]

Shin, J. H. Dementia epidemiology fact sheet 2022. Annals of Rehabilitation Medicine, 2022, 46(2): 53–59. https://doi.org/10.5535/arm.22027

[16]

Selkoe, D. J., Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25years. EMBO Molecular Medicine, 2016, 8(6): 595–608. https://doi.org/10.15252/emmm.201606210

[17]

Mandelkow, E. Tau in alzheimer’s disease. Trends in Cell Biology, 1998, 8(11): 425–427.[LinkOut]. https://doi.org/10.1016/S0962-8924(98)01368-3

[18]

Guo, T. T., Zhang, D. H., Zeng, Y. Z., Huang, T. Y., Xu, H. X., Zhao, Y. J. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Molecular Neurodegeneration, 2020, 15: 40. https://doi.org/10.1186/s13024-020-00391-7

[19]

Karl, H. The case for rejecting the amyloid cascade hypothesis. Nature Neuroscience, 2015, 18(6): 794–799. https://doi.org/10.1038/nn.4017

[20]

Mahase, E. Aducanumab: European agency rejects Alzheimer’s drug over efficacy and safety concerns. BMJ, 2021, 375: n3127. https://doi.org/10.1136/bmj.n3127

[21]

Reardon, S. FDA approves Alzheimer’s drug lecanemab amid safety concerns. Nature, 2023, 613(7943): 227–228. https://doi.org/10.1038/d41586-023-00030-3

[22]

Piller, C. Report on trial death stokes Alzheimer’s drug fears. Science, 2023, 380(6641): 122–123. https://doi.org/10.1126/science.adi2242

[23]

Behl, C. Alzheimer’s disease and oxidative stress: Implications for novel therapeutic approaches. Neurobiolog, 1999, 57(3): 301–323. https://doi.org/10.1016/S0301-0082(98)00055-0

[24]

Swerdlow, R. H., Burns, J. M., Khan, S. M. The alzheimer’s disease mitochondrial cascade hypothesis. Journal of Alzheimer’s Disease, 2010, 20(s2): S265–S279. https://doi.org/10.3233/jad-2010-100339

[25]

Baik, S. H., Ramanujan, V. K., Becker, C., Fett, S., Underhill, D. M., Wolf, A. J. Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation. Science Immunology, 2023, 8(84): eade7652. https://doi.org/10.1126/sciimmunol.ade7652

[26]

Mancuso, M., Orsucci, D., Siciliano, G., Murri, L. Mitochondria, mitochondrial DNA and alzheimers disease. what comes first. Current Alzheimer Research, 2008, 5(5): 457–468. https://doi.org/10.2174/156720508785908946

[27]

Chen, W. T., Lu, A., Craessaerts, K., Pavie, B., Sala Frigerio, C., Corthout, N., Qian, X. Y., Laláková, J., Kühnemund, M., Voytyuk, I. et al. Spatial transcriptomics and in situ sequencing to study alzheimer’s disease. Cell, 2020, 182(4): 976–991.e19. https://doi.org/10.1016/j.cell.2020.06.038

[28]

Wang, N. B., Wang, H. Y., Pan, Q., Kang, J., Liang, Z. W., Zhang, R. H. The combination of β-asarone and icariin inhibits amyloid-β and reverses cognitive deficits by promoting mitophagy in models of alzheimer’s disease. Oxidative Medicine and Cellular Longevity, 2021, 2021: 7158444. https://doi.org/10.1155/2021/7158444

[29]

Jung, E. S., Suh, K., Han, J. H., Kim, H., Kang, H. S., Choi, W. S., Mook-Jung, I. Amyloid-β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk-AMPK pathway. Aging Cell, 2022, 21(5): e13623. https://doi.org/10.1111/acel.13623

[30]

Baik, S. H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J. I., Mook-Jung, I. A breakdown in metabolic reprogramming causes microglia dysfunction in alzheimer’s disease. Cell Metabolism, 2019, 30(3): 493–507.e6. https://doi.org/10.1016/j.cmet.2019.06.005

[31]

Schafer, D. P., Stevens, B. Microglia function in central nervous system development and plasticity. Cold Spring Harbor Perspectives in Biology, 2015, 7(10): a020545. https://doi.org/10.1101/cshperspect.a020545

[32]

Frost, J. L., Schafer, D. P. Microglia: Architects of the developing nervous system. Trends in Cell Biology, 2016, 26(8): 587–597. https://doi.org/10.1016/j.tcb.2016.02.006

[33]

Vidal-Itriago, A., Radford, R. A. W., Aramideh, J. A., Maurel, C., Scherer, N. M., Don, E. K., Lee, A., Chung, R. S., Graeber, M. B., Morsch, M. Microglia morphophysiological diversity and its implications for the CNS. Frontiers in Immunology, 2022, 13: 997786. https://doi.org/10.3389/fimmu.2022.997786

[34]

Masuda, T., Sankowski, R., Staszewski, O., Böttcher, C., Amann, L., Sagar, Scheiwe, C., Nessler, S., Kunz, P., van Loo, G. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature, 2019, 566(7744): 388–392. https://doi.org/10.1038/s41586-019-0924-x

[35]

Sankowski, R., Böttcher, C., Masuda, T., Geirsdottir, L., Sagar, Sindram, E., Seredenina, T., Muhs, A., Scheiwe, C., Shah, M. J. et al. Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nature Neuroscience, 2019, 22(12): 2098–2110. https://doi.org/10.1038/s41593-019-0532-y

[36]
Bilbo, S., Stevens, B. Microglia: The brain’s first responders. Cerebrum, 2017, 2017: cer-14-17.
[37]

Donnelly, C. R., Chen, O., Ji, R. R. How do sensory neurons sense danger signals. Trends in Neurosciences, 2020, 43(10): 822–838. https://doi.org/10.1016/j.tins.2020.07.008

[38]

Murao, A., Aziz, M., Wang, H. C., Brenner, M., Wang, P. Release mechanisms of major DAMPs. Apoptosis, 2021, 26: 152–162. https://doi.org/10.1007/s10495-021-01663-3

[39]

Smit, T., Ormel, P. R., Sluijs, J. A., Hulshof, L. A., Middeldorp, J., de Witte, L. D., Hol, E. M., Donega, V. Transcriptomic and functional analysis of Aβ1-42 oligomer-stimulated human monocyte-derived microglia-like cells. Brain, Behavior, and Immunity, 2022, 100: 219–230. https://doi.org/10.1016/j.bbi.2021.12.001

[40]

Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G. Z., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V. et al. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nature Communications, 2021, 12: 3015. https://doi.org/10.1038/s41467-021-23111-1

[41]

Gu, N., Eyo, U. B., Murugan, M., Peng, J. Y., Matta, S., Dong, H. L., Wu, L. J. Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain. Brain, Behavior, and Immunity, 2016, 55: 82–92. https://doi.org/10.1016/j.bbi.2015.11.007

[42]

Rogove, A. D., Lu, W., Tsirka, S. E. Microglial activation and recruitment, but not proliferation, suffice to mediate neurodegeneration. Cell Death & Differentiation, 2002, 9(8): 801–806. https://doi.org/10.1038/sj.cdd.4401041

[43]

Frank-Cannon, T. C., Alto, L. T., McAlpine, F. E., Tansey, M. G. Does neuroinflammation fan the flame in neurodegenerative diseases. Molecular Neurodegeneration, 2009, 4: 47. https://doi.org/10.1186/1750-1326-4-47

[44]

Martinez, F. O., Gordon, S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Reports, 2014, 6: 13. https://doi.org/10.12703/p6-13

[45]

Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M. E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M. et al. Microglia states and nomenclature: A field at its crossroads. Neuron, 2022, 110(21): 3458–3483. https://doi.org/10.1016/j.neuron.2022.10.020

[46]

Durafourt, B. A., Moore, C. S., Zammit, D. A., Johnson, T. A., Zaguia, F., Guiot, M. C., Bar-Or, A., Antel, J. P. Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia, 2012, 60(5): 717–727. https://doi.org/10.1002/glia.22298

[47]

Wu, Z., Zhang, J., Nakanishi, H. Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation. Journal of Neuroimmunology, 2005, 167(1-2): 90–98. https://doi.org/10.1016/j.jneuroim.2005.06.025

[48]

Cherry, J. D., Olschowka, J. A., O’Banion, M. K. Neuroinflammation and M2 microglia: The good, the bad, and the inflamed. Journal of Neuroinflammation, 2014, 11: 98. https://doi.org/10.1186/1742-2094-11-98

[49]

Yao, Y. Y., Ling, E. A., Lu, D. Microglia mediated neuroinflammation - signaling regulation and therapeutic considerations with special reference to some natural compounds. Histol Histopathol, 2020, 35(11): 1229–1250. https://doi.org/10.14670/HH-18-239

[50]

Farris, W., Schütz, S. G., Cirrito, J. R., Shankar, G. M., Sun, X. Y., George, A., Leissring, M. A., Walsh, D. M., Qiu, wei qiao, Holtzman, D. M. et al. Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. The American Journal of Pathology, 2007, 171(1): 241–251. https://doi.org/10.2353/ajpath.2007.070105

[51]

Gratuze, M., Chen, Y., Parhizkar, S., Jain, N., Strickland, M. R., Serrano, J. R., Colonna, M., Ulrich, J. D., Holtzman, D. M. Activated microglia mitigate Aβ-associated tau seeding and spreading. Journal of Experimental Medicine, 2021, 218(8): e20210542. https://doi.org/10.1084/jem.20210542

[52]

Wiseman, S. Brain mechanisms of compulsive alcohol use. Nature Neuroscience, 2021, 24(10): 1342. https://doi.org/10.1038/s41593-021-00930-5

[53]

Udeochu, J. C., Amin, S., Huang, Y. G., Fan, L., Torres, E. R. S., Carling, G. K., Liu, B. Y., McGurran, H., Coronas-Samano, G., Kauwe, G. et al. Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience. Nature Neuroscience, 2023, 26(5): 737–750. https://doi.org/10.1038/s41593-023-01315-6

[54]

Wang, C., Fan, L., Khawaja, R. R., Liu, B. Y., Zhan, L. H., Kodama, L., Chin, M., Li, Y. Q., Le, D., Zhou, Y. G. et al. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nature Communications, 2022, 13: 1969. https://doi.org/10.1038/s41467-022-29552-6

[55]

Saman, S., Lee, N. C. Y., Inoyo, I., Jin, J., Li, Z. H., Doyle, T., McKee, A. C., Hall, G. F. Proteins recruited to exosomes by tau overexpression implicate novel cellular mechanisms linking tau secretion with alzheimer’s disease. Journal of Alzheimer’s Disease, 2014, 40(s1): S47–S70. https://doi.org/10.3233/jad-132135

[56]
Zhu, B., Liu, Y., Hwang, S., Archuleta, K., Huang, H. J., Campos, A., Murad, R., Piña-Crespo, J., Xu, H. X., Huang, T. Y. Trem2 deletion enhances tau dispersion and pathology through microglia exosomes. Molecular Neurodegeneration, 2022, 17(1): 58. https://doi.org/10.1186/s13024-022-00562-8
DOI
[57]

Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., Gan, W. B. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience, 2005, 8(6): 752–758. https://doi.org/10.1038/nn1472

[58]

Gimeno-Bayón, J., López-López, A., Rodríguez, M. J., Mahy, N. Glucose pathways adaptation supports acquisition of activated microglia phenotype. Journal of Neuroscience Research, 2014, 92(6): 723–731. https://doi.org/10.1002/jnr.23356

[59]

Yang, S., Qin, C., Hu, Z. W., Zhou, L. Q., Yu, H. H., Chen, M., Bosco, D. B., Wang, W., Wu, L. J., Tian, D. S. Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system. Neurobiology of Disease, 2021, 152: 105290. https://doi.org/10.1016/j.nbd.2021.105290

[60]

Bernier, L. P., York, E. M., Kamyabi, A., Choi, H. B., Weilinger, N. L., MacVicar, B. A. Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nature Communications, 2020, 11: 1559. https://doi.org/10.1038/s41467-020-15267-z

[61]

Soto-Heredero, G., Gómez de las Heras, M. M., Gabandé-Rodríguez, E., Oller, J., Mittelbrunn, M. Glycolysis–a key player in the inflammatory response. The FEBS Journal, 2020, 287(16): 3350–3369. https://doi.org/10.1111/febs.15327

[62]

Xiang, X.Y., Wind, K., Wiedemann, T., Blume, T., Shi, Y., Briel, N., Beyer, L., Biechele, G., Eckenweber F., Zatcepin, A., et al. Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases. Science Translational Medicine, 2021, 13: eabe5640. https://doi.org/10.1126/scitranslmed.abe5640

[63]

Cheng, J., Zhang, R., Xu, Z., Ke, Y., Sun, R., Yang, H., Zhang, X., Zhen, X., Zheng, L. T. Early glycolytic reprogramming controls microglial inflammatory activation. J Neuroinflammation, 2021, 18(1): 129. https://doi.org/10.1186/s12974-021-02187-y

[64]

Luo, G., Wang, X. F., Cui, Y. C., Cao, Y., Zhao, Z., Zhang, J. F. Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing perioperative neurocognitive disorders. Journal of Neuroinflammation, 2021, 18(1): 267. https://doi.org/10.1186/s12974-021-02318-5

[65]

Choi, H., Choi, Y., Lee, E. J., Kim, H., Lee, Y., Kwon, S., Hwang, D. W., Lee, D. S., Alzheimer’s Disease Neuroimaging Initiative. Hippocampal glucose uptake as a surrogate of metabolic change of microglia in Alzheimer’s disease. J Neuroinflammation, 2021, 18(1): 190. https://doi.org/10.1186/s12974-021-02244-6

[66]

Huang, J. P., van Zijl, P. C. M., Han, X. Q., Dong, C. M., Cheng, G. W. Y., Tse, K. H., Knutsson, L., Chen, L., Lai, J. H. C., Wu, E. X. et al. Alteredd-glucose in brain parenchyma and cerebrospinal fluid of early Alzheimer’s disease detected by dynamic glucose-enhanced MRI. Science Advances, 2020, 6(20): eaba3884. https://doi.org/10.1126/sciadv.aba3884

[67]

March-Diaz, R., Lara-Ureña, N., Romero-Molina, C., Heras-Garvin, A., Ortega-de San Luis, C., Alvarez-Vergara, M. I., Sanchez-Garcia, M. A., Sanchez-Mejias, E., Davila, J. C., Rosales-Nieves, A. E. et al. Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1. Nature Aging, 2021, 1(4): 385–399. https://doi.org/10.1038/s43587-021-00054-2

[68]

Yang, F., Zhao, D. J., Cheng, M., Liu, Y. N., Chen, Z. Y., Chang, J., Dou, Y. mTOR-mediated immunometabolic reprogramming nanomodulators enable sensitive switching of energy deprivation-induced microglial polarization for alzheimer’s disease management. ACS Nano, 2023, 17(16): 15724–15741. https://doi.org/10.1021/acsnano.3c03232

[69]

Petersen, C.A.H., Alikhani, N., Behbahani, H., Wiehager, B., Pavlov, P. F., Alafuzoff I., Leinonen, V., Ito, A., Winblad, B., Glaser, E., et al. The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(35): 13145–13150. https://doi.org/10.1073/pnas.0806192105

[70]

Ulland, T. K., Song, W. M., Huang, S. C. C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y. Y., Cairns, N. J., Kambal, A. et al. TREM2 maintains microglial metabolic fitness in alzheimer’s disease. Cell, 2017, 170(4): 649–663.e13. https://doi.org/10.1016/j.cell.2017.07.023

[71]
Piers, T. M., Cosker, K., Mallach, A., Johnson, G. T., Guerreiro, R., Hardy, J., Pocock, J. M. A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia. The FASEB Journal, 2020, 34(2): 2436–2450. https://doi.org/10.1096/fj.201902447r
DOI
[72]

Zhao, N., Bu, G. J. A TREM2 antibody energizes microglia. Nature Neuroscience, 2023, 26: 366–368. https://doi.org/10.1038/s41593-023-01265-z

[73]

Leng, L. G., Yuan, Z. Q., Pan, R. Y., Su, X., Wang, H., Xue, J., Zhuang, K., Gao, J., Chen, Z. L., Lin, H. et al. Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance. Nature Metabolism, 2022, 4(10): 1287–1305. https://doi.org/10.1038/s42255-022-00643-4

[74]

Fairley, L. H., Lai, K. O., Wong, J. H., Chong, wei jing, Vincent, A. S., D’Agostino, G., Wu, X. T., Naik, R. R., Jayaraman, A., Langley, S. R. et al. Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 2023, 120(8): e2209177120. https://doi.org/10.1073/pnas.2209177120

[75]

Huang, Y., Xu, W., Zhou, R. B. NLRP3 inflammasome activation and cell death. Cellular & Molecular Immunology, 2021, 18(9): 2114–2127. https://doi.org/10.1038/s41423-021-00740-6

[76]

Feng, Y. S., Tan, Z. X., Wu, L. Y., Dong, F., Zhang, F. The involvement of NLRP3 inflammasome in the treatment of Alzheimer’s disease. Ageing Research Reviews, 2020, 64: 101192. https://doi.org/10.1016/j.arr.2020.101192

[77]

Lučiūnaitė, A., McManus, R. M., Jankunec, M., Rácz, I., Dansokho, C., Dalgėdienė, I., Schwartz, S., Brosseron, F., Heneka, M. T. Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia. Journal of Neurochemistry, 2020, 155(6): 650–661. https://doi.org/10.1111/jnc.14945

[78]

Sbai, O., Djelloul, M., Auletta, A., Ieraci, A., Vascotto, C., Perrone, L. RAGE-TXNIP axis drives inflammation in Alzheimer’s by targeting Aβ to mitochondria in microglia. Cell Death & Disease, 2022, 13(4): 302. https://doi.org/10.1038/s41419-022-04758-0

[79]

Stancu, I. C., Cremers, N., Vanrusselt, H., Couturier, J., Vanoosthuyse, A., Kessels, S., Lodder, C., Brône, B., Huaux, F., Octave, J. N. et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathologica, 2019, 137(4): 599–617. https://doi.org/10.1007/s00401-018-01957-y

[80]

Han, S. X., He, Z. J., Jacob, C., Hu, X., Liang, X., Xiao, W. C., Wan, L., Xiao, P., D’Ascenzo, N., Ni, J. Z. et al. Effect of increased IL-1β on expression of HK in alzheimer’s disease. International Journal of Molecular Sciences, 2021, 22(3): 1306. https://doi.org/10.3390/ijms22031306

[81]

Parajuli, B., Sonobe, Y., Horiuchi, H., Takeuchi, H., Mizuno, T., Suzumura, A. Oligomeric amyloid β induces IL-1β processing via production of ROS: Implication in Alzheimer’s disease. Cell Death & Disease, 2013, 4(12): e975. https://doi.org/10.1038/cddis.2013.503

[82]

Aminzadeh, M., Roghani, M., Sarfallah, A., Riazi, G. H. TRPM2 dependence of ROS-induced NLRP3 activation in Alzheimer’s disease. International Immunopharmacology, 2018, 54: 78–85. https://doi.org/10.1016/j.intimp.2017.10.024

[83]

Zhang, X. W., Wang, R. H., Hu, D., Sun, X. Y., Fujioka, H., Lundberg, K., Chan, E. R., Wang, Q. Q., Xu, R., Flanagan, M. E. et al. Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease. Science Advances, 2020, 6(49): eabb8680. https://doi.org/10.1126/sciadv.abb8680

[84]

von Essen, M. R., Hellem, M. N. N., Vinther-Jensen, T., Ammitzbøll, C., Hansen, R. H., Hjermind, L. E., Nielsen, T. T., Nielsen, J. E., Sellebjerg, F. Early intrathecal T helper 17.1 cell activity in Huntington disease. Annals of Neurology, 2020, 87(2): 246–255. https://doi.org/10.1002/ana.25647

[85]

Hou, Y. J., Lautrup, S., Cordonnier, S., Wang, Y., Croteau, D. L., Zavala, E., Zhang, Y. Q., Moritoh, K., O’Connell, J. F., Baptiste, B. A. et al. NAD + supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(8): E1876–E1885. https://doi.org/10.1073/pnas.1718819115

[86]

Lautrup, S., Sinclair, D. A., Mattson, M. P., Fang, E. F. NAD+ in brain aging and neurodegenerative disorders. Cell Metabolism, 2019, 30(4): 630–655. https://doi.org/10.1016/j.cmet.2019.09.001

[87]

Villela, D., Schlesinger, D., Suemoto, C. K., Grinberg, L. T., Rosenberg, C. A microdeletion in Alzheimer’s disease disrupts NAMPT gene. Journal of Genetics, 2014, 93: 535–537. https://doi.org/10.1007/s12041-014-0399-3

[88]

Xing, S. L., Hu, Y. R., Huang, X. J., Shen, D. Z., Chen, C. Nicotinamide phosphoribosyltransferase-related signaling pathway in early Alzheimer’s disease mouse models. Molecular Medicine Reports, 2019, 20(6): E1876–E1885. https://doi.org/10.3892/mmr.2019.10782

[89]

Hu, Y., Huang, Y., Xing, S. L., Chen, C., Shen, D. Z., Chen, J. L. Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease. Biological Research, 2022, 55: 10. https://doi.org/10.1186/s40659-022-00379-1

[90]

Lopatina, O. L., Komleva, Y. K., Malinovskaya, N. A., Panina, Y. A., Morgun, A. V., Salmina, A. B. CD157 and brain immune system in (patho)physiological conditions: Focus on brain plasticity. Frontiers in Immunology, 2020, 11: 585294. https://doi.org/10.3389/fimmu.2020.585294

[91]

Love, S., Barber, R., Wilcock, G. K. Increased poly(ADP-ribosyl)ation of nuclear proteins in Alzheimer’s disease. Brain, 1999, 122(2): 247–253. https://doi.org/10.1093/brain/122.2.247

[92]

Kauppinen, T. M., Suh, S. W., Higashi, Y., Berman, A. E., Escartin, C., Won, S. J., Wang, C., Cho, S. H., Gan, L., Swanson, R. A. Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid Β. Journal of Neuroinflammation, 2011, 8: 152. https://doi.org/10.1186/1742-2094-8-152

[93]

Roboon, J., Hattori, T., Ishii, H., Takarada-Iemata, M., Nguyen, D. T., Heer, C. D., O’Meally, D., Brenner, C., Yamamoto, Y., Okamoto, H. et al. Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide‐induced microglial and astrocytic neuroinflammation by increasing NAD+. Journal of Neurochemistry, 2021, 158(2): 311–327. https://doi.org/10.1111/jnc.15367

[94]

Blacher, E., Dadali, T., Bespalko, A., Haupenthal, V., Grimm, M., Hartmann, T., Lund, F., Stein, R., Levy, A. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Annals of Neurology, 2015, 78(1): 88–103. https://doi.org/10.1002/ana.24425

[95]

Hou, Y. J., Wei, Y., Lautrup, S., Yang, B. M., Wang, Y., Cordonnier, S., Mattson, M. P., Croteau, D. L., Bohr, V. A. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS–STING. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118(37): e2011226118. https://doi.org/10.1073/pnas.2011226118

[96]

Larrick, J. W., Mendelsohn, A. R. Modulation of cGAS-STING pathway by nicotinamide riboside in alzheimer’s disease. Rejuvenation Research, 2021, 24(5): 397–402. https://doi.org/10.1089/rej.2021.0062

[97]

Wu, Q. J., Zhang, T. N., Chen, H. H., Yu, X. F., Lv, J. L., Liu, Y. Y., Liu, Y. S., Zheng, G., Zhao, J. Q., Wei, Y. F. et al. The sirtuin family in health and disease. Signal Transduction and Targeted Therapy, 2022, 7: 402. https://doi.org/10.1038/s41392-022-01257-8

[98]

Imai, S. I., Guarente, L. NAD+ and sirtuins in aging and disease. Trends in Cell Biology, 2014, 24(8): 464–471. https://doi.org/10.1016/j.tcb.2014.04.002

[99]

Stein, L. R., Imai, S. I. The dynamic regulation of NAD metabolism in mitochondria. Trends in Endocrinology & Metabolism, 2012, 23(9): 420–428. https://doi.org/10.1016/j.tem.2012.06.005

[100]

Zhao, Y., Zhang, J. W., Zheng, Y. L., Zhang, Y. X., Zhang, X. J., Wang, H. M., Du, Y., Guan, J., Wang, X. Z., Fu, J. L. NAD+ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway. Journal of Neuroinflammation, 2021, 18: 207. https://doi.org/10.1186/s12974-021-02250-8

[101]

Zhang, J., Wang, C. X., Ying, W. H. SIRT2 and Akt mediate NAD+-induced and NADH-induced increases in the intracellular ATP levels of BV2 microglia under basal conditions. NeuroReport, 2018, 29(2): 65–70. https://doi.org/10.1097/wnr.0000000000000876

[102]

Liu, Q., Sun, Y. M., Huang, H., Chen, C., Wan, J., Ma, L. H., Sun, Y. Y., Miao, H. H., Wu, Y. Q. Sirtuin 3 protects against anesthesia/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation. Journal of Neuroinflammation, 2021, 18: 41. https://doi.org/10.1186/s12974-021-02089-z

[103]

Li, H. Q., Liu, F., Jiang, W. W., Wang, K. X., Cao, X. Z., Zou, J., Zhou, Y. J., Li, Z., Liu, S. D., Cui, X. T. et al. TREM2 ameliorates lipopolysaccharide-induced oxidative stress response and neuroinflammation by promoting Sirtuin3 in BV2 cells. Neurotoxicity Research, 2022, 40(1): 56–65. https://doi.org/10.1007/s12640-021-00459-2

[104]

Xie, J. H., Li, Y. Y., Jin, J. The essential functions of mitochondrial dynamics in immune cells. Cellular & Molecular Immunology, 2020, 17(7): 712–721. https://doi.org/10.1038/s41423-020-0480-1

[105]

Sheridan, C., Martin, S. J. Mitochondrial fission/fusion dynamics and apoptosis. Mitochondrion, 2010, 10(6): 640–648. https://doi.org/10.1016/j.mito.2010.08.005

[106]

Katoh, M., Wu, B., Nguyen, H. B., Thai, T. Q., Yamasaki, R., Lu, H. Y., Rietsch, A. M., Zorlu, M. M., Shinozaki, Y., Saitoh, Y. et al. Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation. Scientific Reports, 2017, 7: 4942. https://doi.org/10.1038/s41598-017-05232-0

[107]

Liu, H. F., Ho, P. W. L., Leung, C. T., Pang, S. Y. Y., Chang, E. E. S., Choi, Z. Y. K., Kung, M. H. W., Ramsden, D. B., Ho, S. L. Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2R1441G mice. Autophagy, 2021, 17(10): 3196–3220. https://doi.org/10.1080/15548627.2020.1850008

[108]

Ho, D. H., Lee, H., Son, I., Seol, W. G2019s LRRK2 promotes mitochondrial fission and increases TNFα-mediated neuroinflammation responses. Animal Cells and Systems, 2019, 23(2): 106–111. https://doi.org/10.1080/19768354.2019.1585948

[109]

Yang, X. H., Xu, Y., Gao, W. T., Wang, L., Zhao, X. N., Liu, G., Fan, K., Liu, S., Hao, H. M., Qu, S. Y. et al. Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro. Frontiers in Neuroscience, 2022, 16: 1036872. https://doi.org/10.3389/fnins.2022.1036872

[110]

Qin, Y. R., Ma, C. Q., Jiang, J. H., Wang, D. P., Zhang, Q. Q., Liu, M. R., Zhao, H. R., Fang, Q., Liu, Y. Artesunate restores mitochondrial fusion-fission dynamics and alleviates neuronal injury in Alzheimer 's disease models. Journal of Neurochemistry, 2022, 162(3): 290–304. https://doi.org/10.1111/jnc.15620

[111]

Xie, N., Wang, C., Lian, Y., Wu, C., Zhang, H., Zhang, Q. Inhibition of mitochondrial fission attenuates aβ-induced microglia apoptosis. Neuroscience, 2014, 256: 36–42. https://doi.org/10.1016/j.neuroscience.2013.10.011

[112]

Park, J., Choi, H., Min, J., Park, S. J., Kim, J., Park, H. J., Kim, B., Chae, J., Yim, M., Lee, D. S. Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells. Journal of Neurochemistry, 2013, 127(2): 221–232. https://doi.org/10.1111/jnc.12361

[113]

Liu, P. F., Zhou, Y. F., Shi, J. Z., Wang, F., Yang, X. J., Zheng, X. H., Wang, Y. R., He, Y. Y., Xie, X. M., Pang, X. B. Myricetin improves pathological changes in 3 × Tg-AD mice by regulating the mitochondria-NLRP3 inflammasome-microglia channel by targeting P38 MAPK signaling pathway. Phytomedicine, 2023, 115: 154801. https://doi.org/10.1016/j.phymed.2023.154801

[114]

Mo, Y. N., Deng, S. Y., Zhang, L. N., Huang, Y., Li, W. C., Peng, Q. Y., Liu, Z. Y., Ai, Y. H. SS-31 reduces inflammation and oxidative stress through the inhibition of Fis1 expression in lipopolysaccharide-stimulated microglia. Biochemical and Biophysical Research Communications, 2019, 520(1): 171–178. https://doi.org/10.1016/j.bbrc.2019.09.077

[115]

Zhong, L. L., Ren, X. S., Ai, Y. H., Liu, Z. Y. SS-31 improves cognitive function in sepsis-associated encephalopathy by inhibiting the Drp1-NLRP3 inflammasome activation. NeuroMolecular Medicine, 2023, 25: 230–241. https://doi.org/10.1007/s12017-022-08730-1

[116]

Fang, E. F., Hou, Y. J., Palikaras, K., Adriaanse, B. A., Kerr, J. S., Yang, B. M., Lautrup, S., Hasan-Olive, M. M., Caponio, D., Dan, X. L. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nature Neuroscience, 2019, 22(3): 401–412. https://doi.org/10.1038/s41593-018-0332-9

[117]

Bingol, B., Sheng, M. Mechanisms of mitophagy: PINK1, parkin, USP30 and beyond. Free Radical Biology and Medicine, 2016, 100: 210–222. https://doi.org/10.1016/j.freeradbiomed.2016.04.015

[118]

Sun, K., Jing, X. Z., Guo, J. C., Yao, X. D., Guo, F. J. Mitophagy in degenerative joint diseases. Autophagy, 2021, 17(9): 2082–2092. https://doi.org/10.1080/15548627.2020.1822097

[119]

Qiu, J., Chen, Y., Zhuo, J., Zhang, L., Liu, J., Wang, B., Sun, D., Yu, S., Lou, H. Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson’s disease model. Neuropharmacology, 2022, 207: 108963. https://doi.org/10.1016/j.neuropharm.2022.108963

[120]

Wang, N., Yang, J. Y., Chen, R. J., Liu, Y. Y., Liu, S. J., Pan, Y. N., Lei, Q. F., Wang, Y. Z., He, L., Song, Y. Q. et al. Ginsenoside Rg1 ameliorates Alzheimer’s disease pathology via restoring mitophagy. Journal of Ginseng Research, 2023, 47(3): 448–457. https://doi.org/10.1016/j.jgr.2022.12.001

[121]
Kitada, M., Ogura, Y., Koya, D. Role of Sirt1 as a regulator of autophagy. In: Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging. Amsterdam: Elsevier, 2016: 89–100. https://doi.org/10.1016/b978-0-12-802937-4.00003-x
DOI
[122]

Zhao, N., Zhang, X. L., Li, B. X., Wang, J., Zhang, C. F., Xu, B. Treadmill exercise improves PINK1/parkin-mediated mitophagy activity against alzheimer’s disease pathologies by upregulated SIRT1-FOXO1/3 axis in APP/PS1 mice. Molecular Neurobiology, 2023, 60(1): 277–291. https://doi.org/10.1007/s12035-022-03035-7

[123]

Zhao, N., Xia, J., Xu, B. Physical exercise may exert its therapeutic influence on Alzheimer’s disease through the reversal of mitochondrial dysfunction via SIRT1-FOXO1/3-PINK1-Parkin-mediated mitophagy. Journal of Sport and Health Science, 2021, 10(1): 1–3. https://doi.org/10.1016/j.jshs.2020.08.009

[124]

Zhong, G., Long, H. P., Zhou, T., Liu, Y. S., Zhao, J. P., Han, J. Y., Yang, X. H., Yu, Y., Chen, F., Shi, S. L. Blood-brain barrier Permeable nanoparticles for Alzheimer’s disease treatment by selective mitophagy of microglia. Biomaterials, 2022, 288: 121690. https://doi.org/10.1016/j.biomaterials.2022.121690

[125]

Han, X., Xu, T., Fang, Q., Zhang, H., Yue, L., Hu, G., Sun, L. Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy. Redox Biology, 2021, 44: 102010. https://doi.org/10.1016/j.redox.2021.102010

Publication history
Copyright
Rights and permissions

Publication history

Received: 21 November 2023
Revised: 13 December 2023
Accepted: 22 December 2023
Published: 16 January 2024

Copyright

© The Author(s) 2023. Aging Research published by Tsinghua University Press.

Rights and permissions

The articles published in this open access journal are distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Return