The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention

Author(s): Sara Merlo, Simona Federica Spampinato, Grazia Ilaria Caruso, Maria Angela Sortino*

Journal Name: Current Neuropharmacology

Volume 18 , Issue 5 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Amyloid-β (Aβ) has long been shown to be critical in Alzheimer’s disease pathophysiology. Microglia contributes to the earliest responses to Aβ buildup, by direct interaction through multiple receptors. Microglial cells operate Aβ clearance and trigger inflammatory/regenerative processes that take place in the long years of silent disease progression that precede symptomatic appearance. But in time and with aging, the fine balance between pro- and anti-inflammatory activity of microglia deranges, negatively impacting its Aβ-clearing ability. Furthermore, in recent years, microglial activation has proven to be much more complex than the mere dichotomic pro/antiinflammatory polarization previously accepted. Microglia can display a wide spectrum of phenotypes, which can even be mixed. On these bases, it is evident that while pharmacological intervention aiding microglia to prolong its ability to cope with Aβ buildup could be extremely relevant, its feasibility is hampered by such high complexity, which still needs to be completely understood.

Keywords: Alzheimer's disease, β-amyloid receptors, TREM2, CD33, neuroinflammation, microglial activation.

Frozza, R.L.; Lourenco, M.V.; De Felice, F.G. Challenges for Alzheimer’s disease therapy: Insights from novel mechanisms beyond memory defects. Front. Neurosci., 2018, 12, 37.
[] [PMID: 29467605]
Cummings, J.; Lee, G.; Ritter, A.; Zhong, K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement. (N. Y.), 2018, 4, 195-214.
[] [PMID: 29955663]
Sperling, R.; Mormino, E.; Johnson, K. The evolution of preclinical Alzheimer’s disease: implications for prevention trials. Neuron, 2014, 84(3), 608-622.
[] [PMID: 25442939]
Merlo, S.; Spampinato, S.F.; Sortino, M.A. Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer’s Disease? CNS Neurosci. Ther., 2019, 25(1), 5-13.
[] [PMID: 30101571]
Merlo, S.; Spampinato, S.F.; Beneventano, M.; Sortino, M.A. The contribution of microglia to early synaptic compensatory responses that precede β-amyloid-induced neuronal death. Sci. Rep., 2018, 8(1), 7297.
[] [PMID: 29740062]
De Strooper, B.; Karran, E. The cellular phase of Alzheimer’s disease. Cell, 2016, 164(4), 603-615.
[] [PMID: 26871627]
Chong, F.P.; Ng, K.Y.; Koh, R.Y.; Chye, S.M. Tau Proteins and Tauopathies in Alzheimer’s Disease. Cell. Mol. Neurobiol., 2018, 38(5), 965-980.
[PMID: 29299792]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002, 297(5580), 353-356.
[] [PMID: 12130773]
Cline, E.N.; Bicca, M.A.; Viola, K.L.; Klein, W.L. The amyloid-β oligomer hypothesis: beginning of the third decade. J. Alzheimers Dis., 2018, 64(s1), S567-S610.
[] [PMID: 29843241]
Kinney, J.W.; Bemiller, S.M.; Murtishaw, A.S.; Leisgang, A.M.; Salazar, A.M.; Lamb, B.T. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement. (N. Y.), 2018, 4, 575-590.
[] [PMID: 30406177]
Caraci, F.; Merlo, S.; Drago, F.; Caruso, G.; Parenti, C.; Sortino, M.A. Rescue of noradrenergic system as a novel pharmacological strategy in the treatment of chronic pain: focus on microglia activation. Front. Pharmacol., 2019, 10, 1024.
[] [PMID: 31572196]
Cai, Z.; Hussain, M.D.; Yan, L.J. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int. J. Neurosci., 2014, 124(5), 307-321.
[] [PMID: 23930978]
Webers, A.; Heneka, M.T.; Gleeson, P.A. The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer’s disease. Immunol. Cell Biol., 2020, 98(1), 28-41.
[PMID: 31654430]
Minter, M.R.; Taylor, J.M.; Crack, P.J. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J. Neurochem., 2016, 136(3), 457-474.
[] [PMID: 26509334]
Beneventano, M.; Spampinato, S.F.; Merlo, S.; Chisari, M.; Platania, P.; Ragusa, M.; Purrello, M.; Nicoletti, F.; Sortino, M.A. Shedding of microvesicles from microglia contributes to the effects induced by metabotropic glutamate receptor 5 activation on neuronal death. Front. Pharmacol., 2017, 8, 812.
[] [PMID: 29170640]
Takatori, S.; Wang, W.; Iguchi, A.; Tomita, T. Genetic risk factors for alzheimer disease: emerging roles of microglia in disease pathomechanisms. Adv. Exp. Med. Biol., 2019, 1118, 83-116.
[] [PMID: 30747419]
Biber, K.; Bhattacharya, A.; Campbell, B.M.; Piro, J.R.; Rohe, M.; Staal, R.G.W.; Talanian, R.V.; Möller, T. Microglial drug targets in ad: opportunities and challenges in drug discovery and development. Front. Pharmacol., 2019, 10, 840.
[] [PMID: 31507408]
Wolf, S.A.; Boddeke, H.W.; Kettenmann, H. Microglia in physiology and disease. Annu. Rev. Physiol., 2017, 79, 619-643.
[] [PMID: 27959620]
Cherry, J.D.; Olschowka, J.A.; O’Banion, M.K. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation, 2014, 11, 98.
[] [PMID: 24889886]
Du, L.; Zhang, Y.; Chen, Y.; Zhu, J.; Yang, Y.; Zhang, H.L. Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol. Neurobiol., 2017, 54(10), 7567-7584.
[] [PMID: 27830532]
Kabba, J.A.; Xu, Y.; Christian, H.; Ruan, W.; Chenai, K.; Xiang, Y.; Zhang, L.; Saavedra, J.M.; Pang, T. Microglia: Housekeeper of the central nervous system. Cell. Mol. Neurobiol., 2018, 38(1), 53-71.
[] [PMID: 28534246]
Ransohoff, R.M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci., 2016, 19(8), 987-991.
[] [PMID: 27459405]
Karran, E.; Mercken, M.; De Strooper, B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov., 2011, 10(9), 698-712.
[] [PMID: 21852788]
Koenigsknecht-Talboo, J.; Landreth, G.E. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci., 2005, 25(36), 8240-8249.
[] [PMID: 16148231]
Weldon, D.T.; Rogers, S.D.; Ghilardi, J.R.; Finke, M.P.; Cleary, J.P.; O’Hare, E.; Esler, W.P.; Maggio, J.E.; Mantyh, P.W. Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J. Neurosci., 1998, 18(6), 2161-2173.
[] [PMID: 9482801]
Cherry, J.D.; Olschowka, J.A.; O’Banion, M.K. Are “resting” microglia more “m2”? Front. Immunol., 2014, 5, 594.
[] [PMID: 25477883]
Jimenez, S.; Baglietto-Vargas, D.; Caballero, C.; Moreno-Gonzalez, I.; Torres, M.; Sanchez-Varo, R.; Ruano, D.; Vizuete, M.; Gutierrez, A.; Vitorica, J. Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J. Neurosci., 2008, 28(45), 11650-11661.
[] [PMID: 18987201]
Chakrabarty, P.; Li, A.; Ceballos-Diaz, C.; Eddy, J.A.; Funk, C.C.; Moore, B.; DiNunno, N.; Rosario, A.M.; Cruz, P.E.; Verbeeck, C.; Sacino, A.; Nix, S.; Janus, C.; Price, N.D.; Das, P.; Golde, T.E. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron, 2015, 85(3), 519-533.
[] [PMID: 25619653]
Chakrabarty, P.; Tianbai, L.; Herring, A.; Ceballos-Diaz, C.; Das, P.; Golde, T.E. Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol. Neurodegener., 2012, 7, 36.
[] [PMID: 22838967]
Guillot-Sestier, M.V.; Doty, K.R.; Gate, D.; Rodriguez, J., Jr; Leung, B.P.; Rezai-Zadeh, K.; Town, T. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron, 2015, 85(3), 534-548.
[] [PMID: 25619654]
Town, T.; Laouar, Y.; Pittenger, C.; Mori, T.; Szekely, C.A.; Tan, J.; Duman, R.S.; Flavell, R.A. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat. Med., 2008, 14(6), 681-687.
[] [PMID: 18516051]
DiChiara, T.; DiNunno, N.; Clark, J.; Bu, R.L.; Cline, E.N.; Rollins, M.G.; Gong, Y.; Brody, D.L.; Sligar, S.G.; Velasco, P.T.; Viola, K.L.; Klein, W.L. Alzheimer’s toxic amyloid beta oligomers: unwelcome visitors to the na/k atpase alpha3 docking station. Yale J. Biol. Med., 2017, 90(1), 45-61.
[PMID: 28356893]
De Felice, F.G.; Vieira, M.N.; Bomfim, T.R.; Decker, H.; Velasco, P.T.; Lambert, M.P.; Viola, K.L.; Zhao, W.Q.; Ferreira, S.T.; Klein, W.L. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc. Natl. Acad. Sci. USA, 2009, 106(6), 1971-1976.
[] [PMID: 19188609]
Zhao, W.Q.; De Felice, F.G.; Fernandez, S.; Chen, H.; Lambert, M.P.; Quon, M.J.; Krafft, G.A.; Klein, W.L. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J., 2008, 22(1), 246-260.
[] [PMID: 17720802]
Texidó, L.; Martín-Satué, M.; Alberdi, E.; Solsona, C.; Matute, C. Amyloid β peptide oligomers directly activate NMDA receptors. Cell Calcium, 2011, 49(3), 184-190.
[] [PMID: 21349580]
Zhang, Y.; Zhao, Y.; Zhang, L.; Yu, W.; Wang, Y.; Chang, W. Cellular prion protein as a receptor of toxic amyloid-β42 oligomers is important for Alzheimer’s disease. Front. Cell. Neurosci., 2019, 13, 339.
[] [PMID: 31417361]
Copani, A.; Caraci, F.; Hoozemans, J.J.; Calafiore, M.; Sortino, M.A.; Nicoletti, F. The nature of the cell cycle in neurons: focus on a “non-canonical” pathway of DNA replication causally related to death. Biochim. Biophys. Acta, 2007, 1772(4), 409-412.
[] [PMID: 17196375]
Frasca, G.; Carbonaro, V.; Merlo, S.; Copani, A.; Sortino, M.A. Integrins mediate beta-amyloid-induced cell-cycle activation and neuronal death. J. Neurosci. Res., 2008, 86(2), 350-355.
[] [PMID: 17828768]
Herrup, K.; Neve, R.; Ackerman, S.L.; Copani, A. Divide and die: cell cycle events as triggers of nerve cell death. J. Neurosci., 2004, 24(42), 9232-9239.
[] [PMID: 15496657]
Merlo, S.; Basile, L.; Giuffrida, M.L.; Sortino, M.A.; Guccione, S.; Copani, A. Identification of 5-Methoxyflavone as a novel dna polymerase-beta inhibitor and neuroprotective agent against beta-amyloid toxicity. J. Nat. Prod., 2015, 78(11), 2704-2711.
[] [PMID: 26517378]
Copani, A.; Sortino, M.A.; Caricasole, A.; Chiechio, S.; Chisari, M.; Battaglia, G.; Giuffrida-Stella, A.M.; Vancheri, C.; Nicoletti, F. Erratic expression of DNA polymerases by beta-amyloid causes neuronal death. FASEB J., 2002, 16(14), 2006-2008.
[] [PMID: 12397084]
Canale, C.; Seghezza, S.; Vilasi, S.; Carrotta, R.; Bulone, D.; Diaspro, A.; San Biagio, P.L.; Dante, S. Different effects of Alzheimer’s peptide Aβ(1-40) oligomers and fibrils on supported lipid membranes. Biophys. Chem., 2013, 182, 23-29.
[] [PMID: 23998637]
Kagan, B.L.; Hirakura, Y.; Azimov, R.; Azimova, R.; Lin, M.C. The channel hypothesis of Alzheimer’s disease: current status. Peptides, 2002, 23(7), 1311-1315.
[] [PMID: 12128087]
Bode, D.C.; Baker, M.D.; Viles, J.H. Ion channel formation by amyloid-β42 oligomers but not amyloid-β40 in cellular membranes. J. Biol. Chem., 2017, 292(4), 1404-1413.
[] [PMID: 27927987]
Drolle, E.; Hane, F.; Lee, B.; Leonenko, Z. Atomic force microscopy to study molecular mechanisms of amyloid fibril formation and toxicity in Alzheimer’s disease. Drug Metab. Rev., 2014, 46(2), 207-223.
[] [PMID: 24495298]
Mohamed, A.; Posse de Chaves, E. Aβ internalization by neurons and glia. Int. J. Alzheimers Dis., 2011, 2011, 127984
[] [PMID: 21350608]
Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol., 2018, 14, 450-464.
[] [PMID: 29080524]
Caruso, G.; Fresta, C.G.; Musso, N.; Giambirtone, M.; Grasso, M.; Spampinato, S.F.; Merlo, S.; Drago, F.; Lazzarino, G.; Sortino, M.A.; Lunte, S.M.; Caraci, F. Carnosine prevents aβ-induced oxidative stress and inflammation in microglial cells: a key role of TGF-β1. Cells, 2019, 8(1), E64
[] [PMID: 30658430]
Caruso, G.; Spampinato, S.F.; Cardaci, V.; Caraci, F.; Sortino, M.A.; Merlo, S. beta-amyloid and oxidative stress: perspectives in drug development. Curr. Pharm. Des., 2019, 25(45), 4771-4781.
[] [PMID: 31814548]
De Felice, F.G.; Velasco, P.T.; Lambert, M.P.; Viola, K.; Fernandez, S.J.; Ferreira, S.T.; Klein, W.L. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem., 2007, 282(15), 11590-11601.
[] [PMID: 17308309]
Reddy, P.H. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease. Exp. Neurol., 2009, 218(2), 286-292.
[] [PMID: 19358844]
Mattson, M.P.; Cheng, B.; Davis, D.; Bryant, K.; Lieberburg, I.; Rydel, R.E. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci., 1992, 12(2), 376-389.
[] [PMID: 1346802]
Doens, D.; Fernández, P.L. Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis. J. Neuroinflammation, 2014, 11, 48.
[] [PMID: 24625061]
Dionisio-Santos, D.A.; Olschowka, J.A.; O’Banion, M.K. Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease. J. Neuroinflammation, 2019, 16(1), 74.
[] [PMID: 30953557]
Gabande-Rodriguez, E.; Keane, L.; Capasso, M. Microglial phagocytosis in aging and Alzheimer’s disease. J. Neurosci. Res., 2019.
[PMID: 30942936]
Clayton, K.A.; Van Enoo, A.A.; Ikezu, T. Alzheimer’s disease: the role of microglia in brain homeostasis and proteopathy. Front. Neurosci., 2017, 11, 680.
[] [PMID: 29311768]
Yanamadala, V.; Friedlander, R.M. Complement in neuroprotection and neurodegeneration. Trends Mol. Med., 2010, 16(2), 69-76.
[] [PMID: 20116331]
van der Kleij, H.; Charles, N.; Karimi, K.; Mao, Y.K.; Foster, J.; Janssen, L.; Chang Yang, P.; Kunze, W.; Rivera, J.; Bienenstock, J. Evidence for neuronal expression of functional Fc (epsilon and gamma) receptors. J. Allergy Clin. Immunol., 2010, 125(3), 757-760.
[] [PMID: 20132972]
Cattaneo, F.; Guerra, G.; Ammendola, R. Expression and signaling of formyl-peptide receptors in the brain. Neurochem. Res., 2010, 35(12), 2018-2026.
[] [PMID: 21042851]
Husemann, J.; Loike, J.D.; Anankov, R.; Febbraio, M.; Silverstein, S.C. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia, 2002, 40(2), 195-205.
[] [PMID: 12379907]
Okun, E.; Griffioen, K.J.; Mattson, M.P. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci., 2011, 34(5), 269-281.
[] [PMID: 21419501]
Yan, S.D.; Chen, X.; Fu, J.; Chen, M.; Zhu, H.; Roher, A.; Slattery, T.; Zhao, L.; Nagashima, M.; Morser, J.; Migheli, A.; Nawroth, P.; Stern, D.; Schmidt, A.M. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature, 1996, 382(6593), 685-691.
[] [PMID: 8751438]
Takata, K.; Kitamura, Y. Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer’s disease: tangle formation, amyloid-β, and microglia in Alzheimer’s disease. J. Pharmacol. Sci., 2012, 118(3), 331-337.
[] [PMID: 22382659]
Scaffidi, P.; Misteli, T.; Bianchi, M.E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature, 2002, 418(6894), 191-195.
[] [PMID: 12110890]
Vijayakumar, E.C.; Bhatt, L.K.; Prabhavalkar, K.S. High mobility group box-1 (hmgb1): a potential target in therapeutics. Curr. Drug Targets, 2019, 20(14), 1474-1485.
[] [PMID: 31215389]
Takata, K.; Kitamura, Y.; Kakimura, J.; Shibagaki, K.; Tsuchiya, D.; Taniguchi, T.; Smith, M.A.; Perry, G.; Shimohama, S. Role of high mobility group protein-1 (HMG1) in amyloid-beta homeostasis. Biochem. Biophys. Res. Commun., 2003, 301(3), 699-703.
[] [PMID: 12565837]
Takata, K.; Takada, T.; Ito, A.; Asai, M.; Tawa, M.; Saito, Y.; Ashihara, E.; Tomimoto, H.; Kitamura, Y.; Shimohama, S. Microglial amyloid-β1-40 phagocytosis dysfunction is caused by high-mobility group box protein-1: implications for the pathological progression of Alzheimer’s disease. Int. J. Alzheimers Dis., 2012, 2012, 685739
[] [PMID: 22645697]
Sinagra, T.; Merlo, S.; Spampinato, S.F.; Pasquale, R.D.; Sortino, M.A. High mobility group box 1 contributes to wound healing induced by inhibition of dipeptidylpeptidase 4 in cultured keratinocytes. Front. Pharmacol., 2015, 6, 126.
[] [PMID: 26136686]
Straino, S.; Di Carlo, A.; Mangoni, A.; De Mori, R.; Guerra, L.; Maurelli, R.; Panacchia, L.; Di Giacomo, F.; Palumbo, R.; Di Campli, C.; Uccioli, L.; Biglioli, P.; Bianchi, M.E.; Capogrossi, M.C.; Germani, A. High-mobility group box 1 protein in human and murine skin: involvement in wound healing. J. Invest. Dermatol., 2008, 128(6), 1545-1553.
[] [PMID: 18239618]
Bortolotto, V.; Grilli, M. Every cloud has a silver lining: proneurogenic effects of aβ oligomers and hmgb-1 via activation of the rage-nf-κb axis. CNS Neurol. Disord. Drug Targets, 2017, 16(10), 1066-1079.
[] [PMID: 27488419]
Malik, M.; Parikh, I.; Vasquez, J.B.; Smith, C.; Tai, L.; Bu, G.; LaDu, M.J.; Fardo, D.W.; Rebeck, G.W.; Estus, S. Genetics ignite focus on microglial inflammation in Alzheimer’s disease. Mol. Neurodegener., 2015, 10, 52.
[] [PMID: 26438529]
Zhao, Y.; Wu, X.; Li, X.; Jiang, L.L.; Gui, X.; Liu, Y.; Sun, Y.; Zhu, B.; Pina-Crespo, J.C.; Zhang, M.; Zhang, N.; Chen, X.; Bu, G.; An, Z.; Huang, T.Y.; Xu, H. trem2 is a receptor for betaamyloid that mediates microglial function. Neuron, 2018, 97(5), 1023-1031. e1027
Zhong, L.; Wang, Z.; Wang, D.; Wang, Z.; Martens, Y.A.; Wu, L.; Xu, Y.; Wang, K.; Li, J.; Huang, R.; Can, D.; Xu, H.; Bu, G.; Chen, X.F. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Mol. Neurodegener., 2018, 13(1), 15.
[] [PMID: 29587871]
Jin, S.C.; Benitez, B.A.; Karch, C.M.; Cooper, B.; Skorupa, T.; Carrell, D.; Norton, J.B.; Hsu, S.; Harari, O.; Cai, Y.; Bertelsen, S.; Goate, A.M.; Cruchaga, C. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum. Mol. Genet., 2014, 23(21), 5838-5846.
[] [PMID: 24899047]
Jonsson, T.; Stefansson, H.; Steinberg, S.; Jonsdottir, I.; Jonsson, P.V.; Snaedal, J.; Bjornsson, S.; Huttenlocher, J.; Levey, A.I.; Lah, J.J.; Rujescu, D.; Hampel, H.; Giegling, I.; Andreassen, O.A.; Engedal, K.; Ulstein, I.; Djurovic, S.; Ibrahim-Verbaas, C.; Hofman, A.; Ikram, M.A.; van Duijn, C.M.; Thorsteinsdottir, U.; Kong, A.; Stefansson, K. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med., 2013, 368(2), 107-116.
[] [PMID: 23150908]
Yeh, F.L.; Hansen, D.V.; Sheng, M. TREM2, Microglia, and Neurodegenerative Diseases. Trends Mol. Med., 2017, 23(6), 512-533.
[] [PMID: 28442216]
Lee, C.Y.D.; Daggett, A.; Gu, X.; Jiang, L.L.; Langfelder, P.; Li, X.; Wang, N.; Zhao, Y.; Park, C.S.; Cooper, Y.; Ferando, I.; Mody, I.; Coppola, G.; Xu, H.; Yang, X.W. elevated trem2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in alzheimer's disease models. Neuron, 2018, 97(5), 1032-1048. e1035
Wang, Y.; Ulland, T.K.; Ulrich, J.D.; Song, W.; Tzaferis, J.A.; Hole, J.T.; Yuan, P.; Mahan, T.E.; Shi, Y.; Gilfillan, S.; Cella, M.; Grutzendler, J.; DeMattos, R.B.; Cirrito, J.R.; Holtzman, D.M.; Colonna, M. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med., 2016, 213(5), 667-675.
[] [PMID: 27091843]
Yuan, P.; Condello, C.; Keene, C.D.; Wang, Y.; Bird, T.D.; Paul, S.M.; Luo, W.; Colonna, M.; Baddeley, D.; Grutzendler, J. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron, 2016, 90(4), 724-739.
[] [PMID: 27196974]
Jay, T.R.; Miller, C.M.; Cheng, P.J.; Graham, L.C.; Bemiller, S.; Broihier, M.L.; Xu, G.; Margevicius, D.; Karlo, J.C.; Sousa, G.L.; Cotleur, A.C.; Butovsky, O.; Bekris, L.; Staugaitis, S.M.; Leverenz, J.B.; Pimplikar, S.W.; Landreth, G.E.; Howell, G.R.; Ransohoff, R.M.; Lamb, B.T. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med., 2015, 212(3), 287-295.
[] [PMID: 25732305]
Tanzi, R.E. TREM2 and Risk of Alzheimer’s Disease--Friend or Foe? N. Engl. J. Med., 2015, 372(26), 2564-2565.
[] [PMID: 26107057]
Udeochu, J.; Sayed, F.A.; Gan, L. TREM2 and Amyloid Beta: A Love-Hate Relationship. Neuron, 2018, 97(5), 991-993.
[] [PMID: 29518360]
Jay, T.R.; Hirsch, A.M.; Broihier, M.L.; Miller, C.M.; Neilson, L.E.; Ransohoff, R.M.; Lamb, B.T.; Landreth, G.E. Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease. J. Neurosci., 2017, 37(3), 637-647.
[] [PMID: 28100745]
Zheng, H.; Jia, L.; Liu, C.C.; Rong, Z.; Zhong, L.; Yang, L.; Chen, X.F.; Fryer, J.D.; Wang, X.; Zhang, Y.W.; Xu, H.; Bu, G. TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway. J. Neurosci., 2017, 37(7), 1772-1784.
[] [PMID: 28077724]
Zhong, L.; Chen, X.F.; Wang, T.; Wang, Z.; Liao, C.; Wang, Z.; Huang, R.; Wang, D.; Li, X.; Wu, L.; Jia, L.; Zheng, H.; Painter, M.; Atagi, Y.; Liu, C.C.; Zhang, Y.W.; Fryer, J.D.; Xu, H.; Bu, G. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J. Exp. Med., 2017, 214(3), 597-607.
[] [PMID: 28209725]
Suárez-Calvet, M.; Morenas-Rodríguez, E.; Kleinberger, G.; Schlepckow, K.; Araque Caballero, M.A.; Franzmeier, N.; Capell, A.; Fellerer, K.; Nuscher, B.; Eren, E.; Levin, J.; Deming, Y.; Piccio, L.; Karch, C.M.; Cruchaga, C.; Shaw, L.M.; Trojanowski, J.Q.; Weiner, M.; Ewers, M.; Haass, C. Alzheimer’s Disease Neuroimaging Initiative. Early increase of CSF sTREM2 in Alzheimer’s disease is associated with tau related-neurodegeneration but not with amyloid-β pathology. Mol. Neurodegener., 2019, 14(1), 1.
[] [PMID: 30630532]
Ewers, M.; Franzmeier, N.; Suárez-Calvet, M.; Morenas-Rodriguez, E.; Caballero, M.A.A.; Kleinberger, G.; Piccio, L.; Cruchaga, C.; Deming, Y.; Dichgans, M.; Trojanowski, J.Q.; Shaw, L.M.; Weiner, M.W.; Haass, C. Alzheimer’s Disease Neuroimaging Initiative. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Sci. Transl. Med., 2019, 11(507), eaav6221
[] [PMID: 31462511]
Deming, Y.; Filipello, F.; Cignarella, F.; Cantoni, C.; Hsu, S.; Mikesell, R.; Li, Z.; Del-Aguila, J.L.; Dube, U.; Farias, F.G.; Bradley, J.; Budde, J.; Ibanez, L.; Fernandez, M.V.; Blennow, K.; Zetterberg, H.; Heslegrave, A.; Johansson, P.M.; Svensson, J.; Nellgård, B.; Lleo, A.; Alcolea, D.; Clarimon, J.; Rami, L.; Molinuevo, J.L.; Suárez-Calvet, M.; Morenas-Rodríguez, E.; Kleinberger, G.; Ewers, M.; Harari, O.; Haass, C.; Brett, T.J.; Benitez, B.A.; Karch, C.M.; Piccio, L.; Cruchaga, C. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Sci. Transl. Med., 2019, 11(505), eaau2291
[] [PMID: 31413141]
Yao, H.; Coppola, K.; Schweig, J.E.; Crawford, F.; Mullan, M.; Paris, D. Distinct signaling pathways regulate TREM2 phagocytic and NFκB antagonistic activities. Front. Cell. Neurosci., 2019, 13, 457.
[] [PMID: 31649511]
Crocker, P.R.; Paulson, J.C.; Varki, A. Siglecs and their roles in the immune system. Nat. Rev. Immunol., 2007, 7(4), 255-266.
[] [PMID: 17380156]
Lajaunias, F.; Dayer, J.M.; Chizzolini, C. Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. Eur. J. Immunol., 2005, 35(1), 243-251.
[] [PMID: 15597323]
Naj, A.C.; Jun, G.; Beecham, G.W.; Wang, L.S.; Vardarajan, B.N.; Buros, J.; Gallins, P.J.; Buxbaum, J.D.; Jarvik, G.P.; Crane, P.K.; Larson, E.B.; Bird, T.D.; Boeve, B.F.; Graff-Radford, N.R.; De Jager, P.L.; Evans, D.; Schneider, J.A.; Carrasquillo, M.M.; Ertekin-Taner, N.; Younkin, S.G.; Cruchaga, C.; Kauwe, J.S.; Nowotny, P.; Kramer, P.; Hardy, J.; Huentelman, M.J.; Myers, A.J.; Barmada, M.M.; Demirci, F.Y.; Baldwin, C.T.; Green, R.C.; Rogaeva, E.; St George-Hyslop, P.; Arnold, S.E.; Barber, R.; Beach, T.; Bigio, E.H.; Bowen, J.D.; Boxer, A.; Burke, J.R.; Cairns, N.J.; Carlson, C.S.; Carney, R.M.; Carroll, S.L.; Chui, H.C.; Clark, D.G.; Corneveaux, J.; Cotman, C.W.; Cummings, J.L.; DeCarli, C.; DeKosky, S.T.; Diaz-Arrastia, R.; Dick, M.; Dickson, D.W.; Ellis, W.G.; Faber, K.M.; Fallon, K.B.; Farlow, M.R.; Ferris, S.; Frosch, M.P.; Galasko, D.R.; Ganguli, M.; Gearing, M.; Geschwind, D.H.; Ghetti, B.; Gilbert, J.R.; Gilman, S.; Giordani, B.; Glass, J.D.; Growdon, J.H.; Hamilton, R.L.; Harrell, L.E.; Head, E.; Honig, L.S.; Hulette, C.M.; Hyman, B.T.; Jicha, G.A.; Jin, L.W.; Johnson, N.; Karlawish, J.; Karydas, A.; Kaye, J.A.; Kim, R.; Koo, E.H.; Kowall, N.W.; Lah, J.J.; Levey, A.I.; Lieberman, A.P.; Lopez, O.L.; Mack, W.J.; Marson, D.C.; Martiniuk, F.; Mash, D.C.; Masliah, E.; McCormick, W.C.; McCurry, S.M.; McDavid, A.N.; McKee, A.C.; Mesulam, M.; Miller, B.L.; Miller, C.A.; Miller, J.W.; Parisi, J.E.; Perl, D.P.; Peskind, E.; Petersen, R.C.; Poon, W.W.; Quinn, J.F.; Rajbhandary, R.A.; Raskind, M.; Reisberg, B.; Ringman, J.M.; Roberson, E.D.; Rosenberg, R.N.; Sano, M.; Schneider, L.S.; Seeley, W.; Shelanski, M.L.; Slifer, M.A.; Smith, C.D.; Sonnen, J.A.; Spina, S.; Stern, R.A.; Tanzi, R.E.; Trojanowski, J.Q.; Troncoso, J.C.; Van Deerlin, V.M.; Vinters, H.V.; Vonsattel, J.P.; Weintraub, S.; Welsh-Bohmer, K.A.; Williamson, J.; Woltjer, R.L.; Cantwell, L.B.; Dombroski, B.A.; Beekly, D.; Lunetta, K.L.; Martin, E.R.; Kamboh, M.I.; Saykin, A.J.; Reiman, E.M.; Bennett, D.A.; Morris, J.C.; Montine, T.J.; Goate, A.M.; Blacker, D.; Tsuang, D.W.; Hakonarson, H.; Kukull, W.A.; Foroud, T.M.; Haines, J.L.; Mayeux, R.; Pericak-Vance, M.A.; Farrer, L.A.; Schellenberg, G.D. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet., 2011, 43(5), 436-441.
[] [PMID: 21460841]
Zhao, L. CD33 in Alzheimer’s Disease - biology, pathogenesis, and therapeutics: A mini-review. Gerontology, 2019, 65(4), 323-331.
[] [PMID: 30541012]
Estus, S.; Shaw, B.C.; Devanney, N.; Katsumata, Y.; Press, E.E.; Fardo, D.W. Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol., 2019, 138(2), 187-199.
[] [PMID: 30949760]
Griciuc, A.; Patel, S.; Federico, A.N.; Choi, S.H.; Innes, B.J.; Oram, M.K.; Cereghetti, G.; McGinty, D.; Anselmo, A.; Sadreyev, R.I.; Hickman, S.E.; El Khoury, J.; Colonna, M.; Tanzi, R.E. trem2 acts downstream of cd33 in modulating microglial pathology in alzheimer's disease., Neuron, 2019, 103(5), 820-835. e827.
Griciuc, A.; Serrano-Pozo, A.; Parrado, A.R.; Lesinski, A.N.; Asselin, C.N.; Mullin, K.; Hooli, B.; Choi, S.H.; Hyman, B.T.; Tanzi, R.E. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron, 2013, 78(4), 631-643.
[] [PMID: 23623698]
Paolicelli, R.C.; Bolasco, G.; Pagani, F.; Maggi, L.; Scianni, M.; Panzanelli, P.; Giustetto, M.; Ferreira, T.A.; Guiducci, E.; Dumas, L.; Ragozzino, D.; Gross, C.T. Synaptic pruning by microglia is necessary for normal brain development. Science, 2011, 333(6048), 1456-1458.
[] [PMID: 21778362]
Neumann, H.; Kotter, M.R.; Franklin, R.J. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain, 2009, 132(Pt 2), 288-295.
[] [PMID: 18567623]
Ayata, P.; Badimon, A.; Strasburger, H.J.; Duff, M.K.; Montgomery, S.E.; Loh, Y.E.; Ebert, A.; Pimenova, A.A.; Ramirez, B.R.; Chan, A.T.; Sullivan, J.M.; Purushothaman, I.; Scarpa, J.R.; Goate, A.M.; Busslinger, M.; Shen, L.; Losic, B.; Schaefer, A. Epigenetic regulation of brain region-specific microglia clearance activity. Nat. Neurosci., 2018, 21(8), 1049-1060.
[] [PMID: 30038282]
Datta, M.; Staszewski, O.; Raschi, E.; Frosch, M.; Hagemeyer, N.; Tay, T.L.; Blank, T.; Kreutzfeldt, M.; Merkler, D.; Ziegler-Waldkirch, S.; Matthias, P.; Meyer-Luehmann, M.; Prinz, M. Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a contextdependent manner. immunity, 2018, 48(3), 514-529. e516.
Zhu, X.; Wang, S.; Yu, L.; Jin, J.; Ye, X.; Liu, Y.; Xu, Y. HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer’s disease. Aging Cell, 2017, 16(5), 1073-1082.
[] [PMID: 28771976]
Janczura, K.J.; Volmar, C.H.; Sartor, G.C.; Rao, S.J.; Ricciardi, N.R.; Lambert, G.; Brothers, S.P.; Wahlestedt, C. Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc. Natl. Acad. Sci. USA, 2018, 115(47), E11148-E11157.
[] [PMID: 30397132]
Bao, J.; Zheng, L.; Zhang, Q.; Li, X.; Zhang, X.; Li, Z.; Bai, X.; Zhang, Z.; Huo, W.; Zhao, X.; Shang, S.; Wang, Q.; Zhang, C.; Ji, J. Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia. Protein Cell, 2016, 7(6), 417-433.
[] [PMID: 27209302]
Alexandrov, P.N.; Zhao, Y.; Jones, B.M.; Bhattacharjee, S.; Lukiw, W.J. Expression of the phagocytosis-essential protein TREM2 is down-regulated by an aluminum-induced miRNA-34a in a murine microglial cell line. J. Inorg. Biochem., 2013, 128, 267-269.
[] [PMID: 23778113]
Zhao, Y.; Bhattacharjee, S.; Jones, B.M.; Dua, P.; Alexandrov, P.N.; Hill, J.M.; Lukiw, W.J. Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a. Neuroreport, 2013, 24(6), 318-323.
[] [PMID: 23462268]
Madadi, S.; Schwarzenbach, H.; Saidijam, M.; Mahjub, R.; Soleimani, M. Potential microRNA-related targets in clearance pathways of amyloid-β: novel therapeutic approach for the treatment of Alzheimer’s disease. Cell Biosci., 2019, 9, 91.
[] [PMID: 31749959]
Cummings, J.; Lee, G.; Ritter, A.; Sabbagh, M.; Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. (N. Y.), 2019, 5, 272-293.
[] [PMID: 31334330]
Ulland, T.K.; Colonna, M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol., 2018, 14(11), 667-675.
[] [PMID: 30266932]
Lue, L.F.; Kuo, Y.M.; Beach, T.; Walker, D.G. Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol. Neurobiol., 2010, 41(2-3), 115-128.
[] [PMID: 20195797]
Parkhurst, C.N.; Yang, G.; Ninan, I.; Savas, J.N.; Yates, J.R., III; Lafaille, J.J.; Hempstead, B.L.; Littman, D.R.; Gan, W.B. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell, 2013, 155(7), 1596-1609.
[] [PMID: 24360280]
Keren-Shaul, H.; Spinrad, A.; Weiner, A.; Matcovitch-Natan, O.; Dvir-Szternfeld, R.; Ulland, T.K.; David, E.; Baruch, K.; Lara-Astaiso, D.; Toth, B.; Itzkovitz, S.; Colonna, M.; Schwartz, M.; Amit, I. A Unique microglia type associated with restricting development of Alzheimer's disease. Cell, 2017, 169(7), 1276-1290 . e1217.
Ulland, T.K.; Song, W.M.; Huang, S.C.; Ulrich, J.D.; Sergushichev, A.; Beatty, W.L.; Loboda, A.A.; Zhou, Y.; Cairns, N.J.; Kambal, A.; Loginicheva, E.; Gilfillan, S.; Cella, M.; Virgin, H.W.; Unanue, E.R.; Wang, Y.; Artyomov, M.N.; Holtzman, D.M.; Colonna, M. TREM2 maintains microglial metabolic fitness in alzheimer's disease. Cell, 2017, 170(4), 649-663. e613.
Hong, S.; Beja-Glasser, V.F.; Nfonoyim, B.M.; Frouin, A.; Li, S.; Ramakrishnan, S.; Merry, K.M.; Shi, Q.; Rosenthal, A.; Barres, B.A.; Lemere, C.A.; Selkoe, D.J.; Stevens, B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 2016, 352(6286), 712-716.
[] [PMID: 27033548]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 30 January, 2020
Page: [446 - 455]
Pages: 10
DOI: 10.2174/1570159X18666200131105418
Price: $65

Article Metrics

PDF: 22