146
Views
0
CrossRef citations to date
0
Altmetric
Review

Potential Alzheimer’s disease drug targets identified through microglial biology research

, , &
Pages 587-602 | Received 20 Jan 2024, Accepted 22 Mar 2024, Published online: 08 Apr 2024

References

  • World Health Organisation (WHO). Global action plan on the public health response to dementia 2017 – 2025. Geneva World Health Organ. 2017;52:1–27.
  • Abubakar MB, Sanusi KO, Ugusman A, et al. Alzheimer’s disease: an update and insights into pathophysiology. Front Aging Neurosci. 2022;14:1–16. doi: 10.3389/fnagi.2022.742408
  • Sierra A, Paolicelli RC, Kettenmann H. Cien años de microglía: milestones in a century of microglial research. Trends Neurosci. 2019;42(11):778–792. doi: 10.1016/j.tins.2019.09.004
  • Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci. 2008;28(33):8354–8360. doi: 10.1523/JNEUROSCI.0616-08.2008
  • Hodges AK, Piers TM, Collier D, et al. Pathways linking Alzheimer’s disease risk genes expressed highly in microglia. Neuroimmunol Neuroinflam. 2021;8:245–268. doi: 10.20517/2347-8659.2020.60
  • Karch CM, Jeng AT, Nowotny P, et al. Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains. PloS One. 2012;7(11):e50976. doi: 10.1371/journal.pone.0050976
  • Wang Z, Zhang Q, Lin JR, et al. Deep post-GWAS analysis identifies potential risk genes and risk variants for Alzheimer’s disease, providing new insights into its disease mechanisms. Sci Rep. 2021;11(1):20511. doi: 10.1038/s41598-021-99352-3
  • Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17(3):157–172. doi: 10.1038/s41582-020-00435-y
  • de Oliveira J, Kucharska E, Garcez ML, et al. Inflammatory cascade in Alzheimer’s disease pathogenesis: a review of experimental findings. Cells. 2021;10(10):2581. doi: 10.3390/cells10102581
  • Kinney JW, Bemiller SM, Murtishaw AS, et al. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv. 2018;4(1):575–590. doi: 10.1016/j.trci.2018.06.014
  • Chai YL, Lee JH, Chong JR, et al. Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy body dementias. J Neuroinflammation. 2023;20(1):111. doi: 10.1186/s12974-023-02789-8
  • Baik SH, Kang S, Lee W, et al. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 2019;30(3):493–507.e6. doi: 10.1016/j.cmet.2019.06.005
  • Meng JX, Zhang Y, Saman D, et al. Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses. Nat Commun. 2022;13(1):2692. doi: 10.1038/s41467-022-30461-x
  • Sierra A, Gottfried-Blackmore AC, McEwen BS, et al. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia. 2007;55(4):412–424. doi: 10.1002/glia.20468
  • Bickford PC, Flowers A, Grimmig, et al. Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases. Exp Gerontol. 2017;94:4–8. doi: 10.1016/j.exger.2017.01.027
  • Holtman IR, Raj DD, Miller JA, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun. 2015;3(1):31. doi: 10.1186/s40478-015-0203-5
  • Edler MK, Mhatre-Winters I, Richardson JR. Microglia in aging and Alzheimer’s disease: a comparative species review. Cells. 2021;10(5):1138. doi: 10.3390/cells10051138
  • Xiao S-Y, Liu Y-J, Lu W, et al. Possible neuropathology of sleep disturbance linking to Alzheimer’s disease: astrocytic and microglial roles. Front Cell Neurosci. 2022;16:875138. doi: 10.3389/fncel.2022.875138
  • Liu S, Meng Y, Wang N, et al. Disturbance of REM sleep exacerbates microglial activation in APP/PS1 mice. Neurobiol Learn Mem. 2023;200:107737. doi: 10.1016/j.nlm.2023.107737
  • Guillot-Sestier MV, Araiz AR, Mela V, et al. Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer’s disease. Commun Biol. 2021;4(1):711. doi: 10.1038/s42003-021-02259-y
  • Whiten DR, Brownjohn PW, Moore S, et al. Tumour necrosis factor induces increased production of extracellular amyloid-β-and α-synuclein-containing aggregates by human Alzheimer’s disease neurons. Brain Commun. 2020;2(2):fcaa146. doi: 10.1093/braincomms/fcaa146
  • Salvadores N, Moreno-Gonzalez I, Gamez N, et al. Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease. Acta Neuropathol Commun. 2022;10(1):31. doi: 10.1186/s40478-022-01332-9
  • Jayaraman A, Htike TT, James R, et al. TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus. Acta Neuropathol Commun. 2021;9(1):159. doi: 10.1186/s40478-021-01264-w
  • Fu P, Peng F. CSF TNF-α levels were associated with conversion from mild cognitive impairment to dementia. PLoS One. 2022;17(10):e0274503. doi: 10.1371/journal.pone.0274503
  • Zhao A, Li Y, Deng Y. TNF receptors are associated with tau pathology and conversion to Alzheimer’s dementia in subjects with mild cognitive impairment. Neurosci Lett. 2020;738:135392. doi: 10.1016/j.neulet.2020.135392
  • Shi J-H, Sun S-C. Tumor necrosis factor receptor-associated factor regulation of Nuclear factor κB and mitogen-activated protein kinase pathways. Front Immunol. 2018;9:1849. doi: 10.3389/fimmu.2018.01849
  • Ofengeim D, Mazzitelli S, Ito Y, et al. RIPK1 mediates a disease-associated microglial response in alzheimer’s disease. Proc Natl Acad Sci USA. 2017;114(41):E8788–97. doi: 10.1073/pnas.1714175114
  • Steeland S, Gorlé N, Vandendriessche C, et al. Counteracting the effects of TNF receptor‐1 has therapeutic potential in Alzheimer’s disease. EMBO Mol Med. 2018;10(4):e8300. doi: 10.15252/emmm.201708300
  • Ou W, Yang J, Simanauskaite J, et al. Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy. J Neuroinflammation. 2021;18(1):312. doi: 10.1186/s12974-021-02332-7
  • Liang T, Zhang Y, Wu S, et al. The role of NLRP3 inflammasome in Alzheimer’s disease and potential therapeutic targets. Front Pharmacol. 2022;13:845185. doi: 10.3389/fphar.2022.845185
  • Xu Y, Yang Y, Chen X, et al. NLRP3 inflammasome in cognitive impairment and pharmacological properties of its inhibitors. Transl Neurodegener. 2023;12(1):49. doi: 10.1186/s40035-023-00381-x
  • Chen X, Wang Y. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol. 2008;9(8):857–865. doi: 10.1038/ni.1636
  • Valenzuela-Arzeta IE, Soto-Rojas LO, Flores-Martinez YM, et al. LPS triggers acute neuroinflammation and parkinsonism involving NLRP3 inflammasome pathway and mitochondrial CI dysfunction in the rat. Int J Mol Sci. 2023;24(5):4628. doi: 10.3390/ijms24054628
  • Ahmed ME, Iyer S, Thangavel R, et al. Co-localization of Glia maturation factor with NLRP3 inflammasome and autophagosome markers in human Alzheimer’s disease brain. J Alzheimer’s Dis. 2017;60(3):1143–1160. doi: 10.3233/JAD-170634
  • Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674–678. doi: 10.1038/nature11729
  • Sharma B, Satija G, Madan A, et al. Role of NLRP3 inflammasome and its inhibitors as emerging therapeutic drug candidate for Alzheimer’s disease: a review of mechanism of activation, regulation, and inhibition. Inflammation. 2023;46(1):56–87. doi: 10.1007/s10753-022-01730-0
  • Han J, Chitu V, Stanley ER, et al. Inhibition of colony stimulating factor‑1 receptor (CSF‑1r) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges. Cell Mol Life Sci. 2022;79(4):219. doi: 10.1007/s00018-022-04225-1
  • Asai H, Ikezu S, Tsunoda S, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18(11):1584–1593. doi: 10.1038/nn.4132
  • Shi Y, Manis M, Long J, et al. Microglia drive ApoE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019;216(11):2546–2561. doi: 10.1084/jem.20190980
  • Spangenberg EE, Lee RJ, Najafi AR, et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain. 2016;139(4):1265–1281. doi: 10.1093/brain/aww016
  • Casali BT, Macpherson KP, Reed-Geaghan EG, et al. Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies. Neurobiol Dis. 2020;142:104956. doi: 10.1016/j.nbd.2020.104956
  • Olmos-Alonso A, Schetters STT, Sri S, et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain. 2016;139(3):891–907. doi: 10.1093/brain/awv379
  • Sun E, Motolani A, Campos L, et al. The pivotal role of NF-κB in the pathogenesis and therapeutics of Alzheimer’s disease. Int J Mol Sci. 2022;23(16):8972. doi: 10.3390/ijms23168972
  • Wang H, Li Y, Ryder JW, et al. Genome-wide RNAseq study of the molecular mechanisms underlying microglia activation in response to pathological tau perturbation in the rTg4510 tau transgenic animal model. Mol Neurodegener. 2018;13(1):65. doi: 10.1186/s13024-018-0296-y
  • Lindsay A, Hickman D, Srinivasan M. A nuclear factor-kappa B inhibiting peptide suppresses innate immune receptors and gliosis in a transgenic mouse model of Alzheimer’s disease. Biomed Pharmacother. 2021;138:111405. doi: 10.1016/j.biopha.2021.111405
  • Wang C, Fan L, Khawaja RR, et al. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022;13(1):1969. doi: 10.1038/s41467-022-29552-6
  • Rusek M, Smith J, El-Khatib K, et al. The role of the JAK/STAT signaling pathway in the pathogenesis of Alzheimer’s disease: new potential treatment target. Int J Mol Sci. 2023;24(1):864. doi: 10.3390/ijms24010864
  • Hu X, Li J, Fu M, et al. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6(1):402. doi: 10.1038/s41392-021-00791-1
  • Przanowski P, Dabrowski M, Ellert-Miklaszewska A, et al. The signal transducers STAT1 and STAT3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia. J Mol Med. 2014;92(3):239–254. doi: 10.1007/s00109-013-1090-5
  • Xiong J, Wang C, Chen H, et al. Aβ-induced microglial cell activation is inhibited by baicalin through the JAK2/STAT3 signaling pathway. Int J Neurosci. 2014;124(8):609–620. doi: 10.3109/00207454.2013.865027
  • Jones RS, Minogue AM, Fitzpatrick O, et al. Inhibition of JAK2 attenuates the increase in inflammatory markers in microglia from APP/PS1 mice. Neurobiol Aging. 2015;36(10):2716–2724. doi: 10.1016/j.neurobiolaging.2015.04.018
  • Choi M, Kim H, Yang EJ, et al. Inhibition of STAT3 phosphorylation attenuates impairments in learning and memory in 5xFAD mice, an animal model of Alzheimer’s disease. J Pharmacol Sci. 2020;143(4):290–299. doi: 10.1016/j.jphs.2020.05.009
  • Kheiri G, Dolatshahi M, Rahmani F, et al. Role of p38/MAPKs in Alzheimer’s disease: implications for amyloid beta toxicity targeted therapy. Rev Neurosci. 2019;30(1):9–30. doi: 10.1515/revneuro-2018-0008
  • Bachstetter AD, Xing B, de Almeida L, et al. Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ). J Neuroinflammation. 2011;8(1):79. doi: 10.1186/1742-2094-8-79
  • Sun A, Liu M, Nguyen XV, et al. P38 MAP kinase is activated at early stages in Alzheimer’s disease brain. Exp Neurol. 2003;183(2):394–405. doi: 10.1016/S0014-4886(03)00180-8
  • Zhu X, Rottkamp CA, Boux H, et al. Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol. 2000;59(10):880–888. doi: 10.1093/jnen/59.10.880
  • Perea JR, García E, Vallés-Saiz L, et al. P38 activation occurs mainly in microglia in the P301S tauopathy mouse model. Sci Rep. 2022;12(1):2130. doi: 10.1038/s41598-022-05980-8
  • Lin H, Dixon SG, Hu W, et al. P38 MAPK is a major regulator of amyloid beta-induced IL-6 expression in human microglia. Mol Neurobiol. 2022;59(9):5284–5298. doi: 10.1007/s12035-022-02909-0
  • Perea JR, Bolós M, Cuadros R, et al. P38 inhibition decreases tau toxicity in microglia and improves their phagocytic function. Mol Neurobiol. 2022;59(3):1632–1648. doi: 10.1007/s12035-021-02715-0
  • Son SH, Lee NR, Gee MS, et al. Chemical knockdown of phosphorylated p38 mitogen-activated protein kinase (MAPK) as a novel approach for the treatment of Alzheimer′s disease. ACS Cent Sci. 2023;9(3):417–426. doi: 10.1021/acscentsci.2c01369
  • Gee MS, Son SH, Jeon SH, et al. A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5xFAD mouse. Alzheimer’s Res Ther. 2020;12(1):45. doi: 10.1186/s13195-020-00617-2
  • Lauro C, Limatola C. Metabolic reprograming of microglia in the regulation of the innate inflammatory response. Front Immunol. 2020;11:493. doi: 10.3389/fimmu.2020.00493
  • Pan RY, He L, Zhang J, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab. 2022;34(4):634–648.e6. doi: 10.1016/j.cmet.2022.02.013.
  • Hu Y, Cao K, Wang F, et al. Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity. Nat Metab. 2022;4(12):1756–1774. doi: 10.1038/s42255-022-00707-5
  • Leng L, Yuan Z, Pan R, et al. Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance. Nat Metab. 2022;4(10):1287–1305. doi: 10.1038/s42255-022-00643-4
  • Pan RY, Ma J, Kong XX, et al. Sodium rutin ameliorates Alzheimer’s disease-like pathology by enhancing microglial amyloid-β clearance. Sci Adv. 2020;5(2):eaau6328. doi: 10.1126/sciadv.aau6328
  • Esposito M, Sherr GL. Epigenetic modifications in Alzheimer’s neuropathology and therapeutics. Front Neurosci. 2019;13:476. doi: 10.3389/fnins.2019.00476
  • Bufill E, Ribosa-Nogué R, Blesa R. The therapeutic potential of epigenetic modifications in Alzheimer’s disease. Alzheimer’s Dis Drug Discov. 2020;9:151–164.
  • Rao JS, Keleshian VL, Klein S, et al. Epigenetic modifications in frontal cortex from Alzheimer’s disease and bipolar disorder patients. Transl Psychiatry. 2012;2(7):e132. doi: 10.1038/tp.2012.55
  • Wang X, Liu L, Jiang X, et al. Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease. Alzheimers Res Ther. 2023;15(1):164. doi: 10.1186/s13195-023-01311-9
  • Gao X, Chen Q, Yao H, et al. Epigenetics in Alzheimer’s disease. Front Aging Neurosci. 2022;14:911635. doi: 10.3389/fnagi.2022.911635
  • Chuang DM, Leng Y, Marinova Z, et al. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci. 2009;32(11):591–601. doi: 10.1016/j.tins.2009.06.002
  • Liu Y, Cheng X, Li H, et al. Non-coding RNAs as novel regulators of neuroinflammation in Alzheimer’s disease. Front Immunol. 2022;13:908076. doi: 10.3389/fimmu.2022.908076
  • Freilich RW, Woodbury ME, Ikezu T, et al. Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia. PloS One. 2013;8(11):e79416. doi: 10.1371/journal.pone.0079416
  • Aloi MS, Prater KE, Sánchez REA, et al. Microglia specific deletion of mir-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures. J Neuroinflammation. 2023;20(1):60. doi: 10.1186/s12974-023-02745-6
  • Qian Q, Zhang J, He FP, et al. Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer’s disease. FASEB J. 2019;33(3):4404–4417. doi: 10.1096/fj.201801846R
  • Zhao J, He Z, Wang J. MicroRNA-124: a key player in microglia-mediated inflammation in neurological diseases. Front Neurosci. 2021;15:771898. doi: 10.3389/fncel.2021.771898
  • Minter MR, Hinterleitner R, Meisel M, et al. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPswe/PS1δE9 murine model of Alzheimer’s disease. Sci Rep. 2017;7(1):10411. doi: 10.1038/s41598-017-11047-w
  • Minter MR, Zhang C, Leone V, et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep. 2016;6(1):30028. doi: 10.1038/srep30028
  • Decandia D, Gelfo F, Landolfo E, et al. Dietary protection against cognitive impairment, neuroinflammation and oxidative stress in Alzheimer’s disease animal models of lipopolysaccharide-induced inflammation. Int J Mol Sci. 2023;24(6):5921. doi: 10.3390/ijms24065921
  • Abdelhamid M, Zhou C, Ohno K, et al. Probiotic bifidobacterium breve prevents memory impairment through the reduction of both amyloid-β production and microglia activation in APP knock-in mouse. J Alzheimer’s Dis. 2022;85(4):1555–1571. doi: 10.3233/JAD-215025
  • Kobayashi Y, Sugahara H, Shimada K, et al. Therapeutic potential of bifidobacterium breve strain a1 for preventing cognitive impairment in Alzheimer’s disease. Sci Rep. 2017;7(1):13510. doi: 10.1038/s41598-017-13368-2
  • Liu N, Yang D, Sun J, et al. Probiotic supplements are effective in people with cognitive impairment: a meta-analysis of randomized controlled trials. Nutr Rev. 2023;81(9):1091–1104. doi: 10.1093/nutrit/nuac113
  • Palasz E, Wilkaniec A, Stanaszek L, et al. Neurotrophic factors and glia crosstalk: possible role in pathobiology of neuroinflammation-related brain disorders. Int J Mol Sci. 2023;24(7):6321. doi: 10.3390/ijms24076321
  • Miranda M, Morici JF, Zanoni MB, et al. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci. 2019;13:363. doi: 10.3389/fncel.2019.00363
  • Zhang J, Rong P, Zhang L, et al. IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis. Sci Adv. 2021;7(12):eabb9888. doi: 10.1126/sciadv.abb9888
  • Connor B, Young D, Yan Q, et al. Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Mol Brain Res. 1997;49(1–2):71–81. doi: 10.1016/S0169-328X(97)00125-3
  • Nagahara A, Merrill D, Coppola G, et al. Neuroprotective effects of BDNF in rodent and primate models of ad nih public access. Nat Med. 2009;15(3):331–337. doi: 10.1038/nm.1912
  • Jiao SS, Shen LL, Zhu C, et al. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease. Transl Psychiatry. 2016;6(10):e907. doi: 10.1038/tp.2016.186
  • Nagahara AH, Mateling M, Kovacs I, et al. Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. J Neurosci. 2013;33(39):15596–15602. doi: 10.1523/JNEUROSCI.5195-12.2013
  • Nigam SM, Xu S, Kritikou J, et al. Exercise and BDNF reduce Aβ production by enhancing α-secretase processing of APP. J Neurochem. 2017;142(2):286–296. doi: 10.1111/jnc.14034
  • Xie Y, Chen X, Li Y, et al. Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways. J Neuroinflammation. 2022;19(1):194. doi: 10.1186/s12974-022-02557-0
  • Islam A, Choudhury ME, Kigami Y, et al. Sustained anti-inflammatory effects of TGF-β1 on microglia/macrophages. Biochimet Biophys Acta – Mol Basis Dis. 2018;1864(3):721–734. doi: 10.1016/j.bbadis.2017.12.022
  • Cao BB, Zhang XX, Du CY, et al. TGF-β1 provides neuroprotection via inhibition of microglial activation in 3-acetylpyridine-induced cerebellar ataxia model rats. Front Neurosci. 2020;14:187. doi: 10.3389/fnins.2020.00187
  • Chen X, Liu Z, Cao BB, et al. TGF-β1 neuroprotection via inhibition of microglial activation in a rat model of Parkinson’s disease. J Neuroimmune Pharmacol. 2017;12(3):433–446. doi: 10.1007/s11481-017-9732-y
  • Kapoor M, Chinnathambi S. TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized tau perspective. J Neuroinflammation. 2023;20(1):72. doi: 10.1186/s12974-023-02751-8
  • Shen WX, Chen JH, Lu JH, et al. TGF-β1 protection against Aβ1–42-induced neuroinflammation and neurodegeneration in rats. Int J Mol Sci. 2014;15(12):22092–22108. doi: 10.3390/ijms151222092
  • Podleśny-Drabiniok A, Marcora E, Goate AM. Microglial phagocytosis: a disease-associated process emerging from Alzheimer’s disease genetics. Trends Neurosci. 2020;43(12):965–979. doi: 10.1016/j.tins.2020.10.002
  • Gu Z, Cao H, Zuo C, et al. TFEB in Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Neurobiol Dis. 2022;173:105855. doi: 10.1016/j.nbd.2022.105855
  • Mawuenyega KG. Decreased clearance of CNS amyloid-β in Alzheimer’s disease. Science. 2010;330(6012):1774. doi: 10.1126/science.1197623
  • Butler CA, Popescu AS, Kitchener EJA, et al. Microglial phagocytosis of neurons in neurodegeneration, and its regulation. J Neurochem. 2021;158(3):621–639. doi: 10.1111/jnc.15327
  • Targa H, Anastacio D. Neuronal hyperexcitability in Alzheimer’s disease: what are the drivers behind this aberrant phenotype? Transl Psychiatry. 2022;12:257. doi: 10.1038/s41398-022-02024-7
  • Novikova G, Kapoor M, Tcw J, et al. Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes. Nat Commun. 2021;12(1):1610. doi: 10.1038/s41467-021-21823-y
  • Bellenguez C, Küçükali F, Jansen IE, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022;54(4):412–436. doi: 10.1038/s41588-022-01024-z
  • Khani M, Gibbons E, Bras J, et al. Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease. Mol Neurodegener. 2022;17(1):3. doi: 10.1186/s13024-021-00505-9
  • Andrews SJ, Renton AE, Fulton-Howard B, et al. The complex genetic architecture of Alzheimer’s disease: novel insights and future directions. EBioMedicine. 2023;90:104511. doi: 10.1016/j.ebiom.2023.104511
  • Jiang T, Tan L, Chen Q, et al. Neurobiology of aging a rare coding variant in TREM2 increases risk for Alzheimer’s disease in han chinese. Neurobiol Aging. 2016;42:217.e1–3. doi: 10.1016/j.neurobiolaging.2016.02.023
  • Hickman S, Kingery N, Ohsumi T, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16(12):1896–1905. doi: 10.1038/nn.3554
  • Hickman SE, El Khoury J. TREM2 and the neuroimmunology of Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):495–498. doi: 10.1016/j.bcp.2013.11.021
  • Wang Y, Ulland TK, Ulrich JD, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213(5):667–675. doi: 10.1084/jem.20151948
  • Zhao N, Qiao W, Li F, et al. Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia. J Exp Med. 2022;219(12):e20212479. doi: 10.1084/jem.20212479
  • Mazaheri F, Snaidero N, Kleinberger G, et al. TREM 2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 2017;18(7):1186–1198. doi: 10.15252/embr.201743922
  • Parhizkar S, Arzberger T, Brendel M, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019;22(2):191–204. doi: 10.1038/s41593-018-0296-9
  • Price BR, Sudduth TL, Weekman EM, et al. Therapeutic targeting of TREM2 by an activating antibody ameliorates amyloid‐beta deposition and improves cognition in the 5xFAD model of Alzheimer’s disease. Alzheimer’s Dement. 2019;17(1):238. doi: 10.1016/j.jalz.2019.06.4559
  • van Lengerich B, Zhan L, Xia D, et al. A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models. Nat Neurosci. 2023;26(3):416–429.
  • Schlepckow K, Monroe KM, Kleinberger G, et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med. 2020;12(4):e11227. doi: 10.15252/emmm.201911227
  • Boza A, Rocío S, Raquel R, et al. Galectin‑3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Acta Neuropathol. 2019;138(2):251–273. doi: 10.1007/s00401-019-02013-z
  • Thu VTA, Hoang TX, Kim JY. 1,25-dihydroxy vitamin DE3 facilitates the M2 polarization and β-amyloid uptake by human microglia in a TREM2-dependent manner. Biomed Res Int. 2023;3483411. doi: 10.1155/2023/3483411
  • Hollingworth P, Harold D, Sims R, et al. Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43(5):429–435. doi: 10.1038/ng.803
  • Walker DG, Whetzel AM, Serrano G, et al. Association of CD33 polymorphism rs3865444 with Alzheimer’s disease pathology and CD33 expression in human cerebral cortex. Neurobiol Aging. 2015;36(2):571–582. doi: 10.1016/j.neurobiolaging.2014.09.023
  • Griciuc A, Federico AN, Natasan J, et al. Gene therapy for Alzheimer’s disease targeting CD33 reduces amyloid beta accumulation and neuroinflammation. Hum Mol Genet. 2020;29(17):2920–2935. doi: 10.1093/hmg/ddaa179
  • Wißfeld J, Nozaki I, Mathews M, et al. Deletion of Alzheimer’s disease-associated CD33 results in an inflammatory human microglia phenotype. Glia. 2021;69(6):1393–1412. doi: 10.1002/glia.23968
  • Aires V, Coulon-Bainier C, Pavlovic A, et al. CD22 blockage restores age-related impairments of microglia surveillance capacity. Front Immunol. 2021;12:684430. doi: 10.3389/fimmu.2021.684430
  • Pluvinage JV, Haney MS, Smith BAH, et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019;568(7751):187–192. doi: 10.1038/s41586-019-1088-4
  • Mishra S, Knupp A, Young JE, et al. Depletion of the AD risk gene Sorl1 causes endo-lysosomal dysfunction in human microglia. Alzheimer’s Dement. 2022;18(S4):e068943. doi: 10.1002/alz.068943
  • Guo X, Tang P, Chen L, et al. Amyloid β-induced redistribution of transcriptional factor EB and lysosomal dysfunction in primary microglial cells. Front Aging Neurosci. 2017;9:228. doi: 10.3389/fnagi.2017.00228
  • Li T, Yin L, Kang X, et al. TFEB acetylation promotes lysosome biogenesis and ameliorates Alzheimer’s disease–relevant phenotypes in mice. J Biol Chem. 2022;298(12):102649. doi: 10.1016/j.jbc.2022.102649
  • Lo CH, Zeng J. Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases. Transl Neurodegener. 2023;12(1):29. doi: 10.1186/s40035-023-00362-0
  • Majumdar A, Capetillo-Zarate E, Cruz D, et al. Degradation of Alzheimer’s amyloid fibrils by microglia requires delivery of CIC-7 to lysosomes. Mol Biol Cell. 2011;22(10):1664–1676. doi: 10.1091/mbc.e10-09-0745
  • Lepiarz-Raba I, Gbadamosi I, Florea R, et al. Metabolic regulation of microglial phagocytosis: implications for Alzheimer’s disease therapeutics. Transl Neurodegener. 2023;12(1):48. doi: 10.1186/s40035-023-00382-w
  • McDonald CL, Hennessy E, Rubio-Araiz A, et al. Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease. Brain Behav Immun. 2016;58:191–200. doi: 10.1016/j.bbi.2016.07.143
  • Rubio-Araiz A, Finucane OM, Keogh S, et al. Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid. J Neuroinflammation. 2018;15(1):247. doi: 10.1186/s12974-018-1281-7
  • Hou Y, Wei Y, Lautrup S, et al. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS – STING. Proc Natl Acad Sci, USA. 2021;118(37):e2011226118. doi: 10.1073/pnas.2011226118
  • Pedicone C, Fernandes S, Dungan OM, et al. Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis. J Cell Sci. 2020;133(5):jcs238030. doi: 10.1242/jcs.238030
  • Shi Q, Chang C, Saliba A, et al. Microglial mTOR activation upregulatesTREM2 and enhances β-amyloid plaque clearance in the 5xFAD Alzheimer’s disease model. J Neurosci. 2022;42(27):5294–5313.
  • Kana O, Brylinski M, Rouge B, et al. Elucidating the druggability of the human proteome with eFindsite. J Comput Aided Mol Des. 2019;33(5):509–519. doi: 10.1007/s10822-019-00197-w
  • Zhang MM, Guo MX, Zhang QP, et al. IL‑1R/C3aR signaling regulates synaptic pruning in the prefrontal cortex of depression. Cell Biosci. 2022;12(1):90. doi: 10.1186/s13578-022-00832-4
  • N’Songo A, Kanekiyo T, Bu G. LRP1 plays a major role in the amyloid-β clearance in microglia. Mol Neurodegener. 2013;8(S1):33. doi: 10.1186/1750-1326-8-S1-P33
  • Yang L, Liu CC, Zheng H, et al. LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways. J Neuroinflammation. 2016;13(1):304. doi: 10.1186/s12974-016-0772-7
  • Dobri AM, Dudău M, Enciu AM, et al. CD36 in Alzheimer’s disease: an overview of molecular mechanisms and therapeutic targeting. Neuroscience. 2021;453:301–311. doi: 10.1016/j.neuroscience.2020.11.003
  • Facci L, Barbierato M, Marinelli C, et al. Toll-like receptors 2, -3 and -4 prime microglia but not astrocytes across central nervous system regions for ATP-dependent interleukin-1β release. Sci Rep. 2014;4(1):6824. doi: 10.1038/srep06824
  • Zhong L, Sheng X, Wang W, et al. Article TREM2 receptor protects against complement- mediated synaptic loss by binding to complement C1q during neurodegeneration ll article TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration. Immunity. 2023;56(8):1794–1808.e8. doi: 10.1016/j.immuni.2023.06.016
  • Zhang X, Tang L, Yang J, et al. Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease. Nat Commun. 2023;14(1):6670. doi: 10.1038/s41467-023-42505-x
  • Zhao P, Xu Y, Fan X, et al. Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5xFAD mice. MAbs. 2022;14(1):2107971. doi: 10.1080/19420862.2022.2107971
  • Wu R, Li X, Xu P, et al. TREM2 protects against cerebral ischemia/reperfusion injury. Mol Brain. 2017;10(1):20. doi: 10.1186/s13041-017-0296-9
  • Zhao Y, Bhattacharjee S, Jones BM, et al. Regulation of TREM22 expression by an NF-kB-sensitive miRNA-34a. Neuroreport. 2013;24(6):318–323. doi: 10.1097/WNR.0b013e32835fb6b0
  • Song S, Yu L, Hasan MN, et al. Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice. Commun Biol. 2022;5(1):35. doi: 10.1038/s42003-021-02984-4
  • Li T, Li X, Huang X, et al. Mitochondriomics reveals the underlying neuroprotective mechanism of TrkB receptor agonist R13 in the 5×FAD mice. Neuropharmacology. 2022;204:108899. doi: 10.1016/j.neuropharm.2021.108899
  • Lloyd AF, Martinez-Muriana A, Hou P, et al. Deep proteomic analysis of human microglia and model systems reveal fundamental biological differences of in vitro and ex vivo cells. bioRxiv. 2022. doi: 10.1101/2022.07.07.498804
  • Cadiz MP, Jensen TD, Sens JP, et al. Culture shock: microglial heterogeneity, activation, and disrupted single ‑ cell microglial networks in vitro. Mol Neurodegener. 2022;17(1):26. doi: 10.1186/s13024-022-00531-1
  • Mancuso R, Van Den Daele J, Fattorelli N, et al. Stem-cell-derived human microglia transplanted in mouse brain to study human disease. Nat Neurosci. 2019;22(12):2111–2116. doi: 10.1038/s41593-019-0525-x
  • Popova G, Soliman SS, Kim CN, et al. Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids. Cell Stem Cell. 2022;28(12):2153–2166.e6. doi: 10.1016/j.stem.2021.08.015
  • Paolicelli RC, Sierra A, Stevens B, et al. Microglia states and nomenclature: a field at its crossroads. Neuron. 2022;110(21):3458–3483. doi: 10.1016/j.neuron.2022.10.020
  • Claire DA, Largeau B, Joao M, et al. Translocator protein-18 kda (TSPO) positron emission tomography (PET) imaging and its clinical impact in neurodegenerative diseases. Int J Mol Sci. 2017;18(4):785. doi: 10.3390/ijms18040785
  • Söderberg L, Johannesson M, Nygren P, et al. Lecanemab, aducanumab, and gantenerumab—binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease. Neurotherapeutics. 2023;20(1):195–206. doi: 10.1007/s13311-022-01308-6
  • Budd Haeberlein S, Aisen P, Barkhof F, et al. Two randomized phase 3 studies of Aducanumab in early Alzheimer’s disease. J Prev Alzheimer’s Dis. 2022;2(9):197–210. doi: 10.14283/jpad.2022.30
  • Cohen S, van Dyck CH, Gee M, et al. Lecanemab clarity AD: quality-of-life results from a randomized, double-blind phase 3 trial in early Alzheimer’s disease. J prev Alzheimer’s dis. 2023;4(10):771–777. doi: 10.14283/jpad.2023.123
  • Plowey ED, Bussiere T, Rajagovindan R, et al. Alzheimer disease neuropathology in a patient previously treated with Aducanumab. Acta Neuropathol. 2022;144(1):143–153. doi: 10.1007/s00401-022-02433-4
  • Cadiz MP, Gibson KA, Todd KT, et al. Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations. J Exp Med. 2024;221(2):e20231363. doi: 10.1084/jem.20231363

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.