Microglia Play an Active Role in Obesity-Associated Cognitive Decline

Cope, Elise C.; LaMarca, Elizabeth A.; Monari, Patrick K.; Olson, Lyra B.; Martinez, Susana; Zych, Anna D.; Katchur, Nicole J.; Gould, Elizabeth

doi:10.1523/jneurosci.0789-18.2018

Cited by 219

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Microglia Play an Active Role in Obesity-Associated Cognitive Decline

Cope, Elise C., LaMarca, Elizabeth A., Monari, Patrick K., Olson, Lyra B., Martinez, Susana, Zych, Anna D., Katchur, Nicole J., Gould, Elizabeth·2018·The Journal of Neuroscience

DOI 10.1523/jneurosci.0789-18.2018

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Abstract

Obesity affects >600 million people worldwide, a staggering number that appears to be on the rise. One of the lesser known consequences of obesity is its deleterious effects on cognition, which have been well documented across many cognitive domains and age groups. To investigate the cellular mechanisms that underlie obesity-associated cognitive decline, we used diet-induced obesity in male mice and found memory impairments along with reductions in dendritic spines, sites of excitatory synapses, increases in the activation of microglia, the brain's resident immune cells, and increases in synaptic profiles within microglia, in the hippocampus, a brain region linked to cognition. We found that partial knockdown of the receptor for fractalkine, a chemokine that can serve as a “find me” cue for microglia, prevented microglial activation and cognitive decline induced by obesity. Furthermore, we found that pharmacological inhibition of microglial activation in obese mice was associated with prevention of both dendritic spine loss and cognitive degradation. Finally, we observed that pharmacological blockade of microglial phagocytosis lessened obesity-associated cognitive decline. These findings suggest that microglia play an active role in obesity-associated cognitive decline by phagocytosis of synapses that are important for optimal function. SIGNIFICANCE STATEMENT Obesity in humans correlates with reduced cognitive function. To investigate the cellular mechanisms underlying this, we used diet-induced obesity in mice and found impaired performance on cognitive tests of hippocampal function. These deficits were accompanied by reduced numbers of dendritic spines, increased microglial activation, and increased synaptic profiles within microglia. Inhibition of microglial activation by transgenic and pharmacological methods prevented cognitive decline and dendritic spine loss in obese mice. Moreover, pharmacological inhibition of the phagocytic activity of microglia was also sufficient to prevent cognitive degradation. This work suggests that microglia may be responsible for obesity-associated cognitive decline and dendritic spine loss.

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Obesity is associated with systemic inflammation, leading to neuroinflammation and cognitive impairment.
“Obesity is associated with systemic inflammation, leading to neuroinflammation and cognitive impairment29.”
From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [29]

Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., et al. (2011) · Science · doi:10.1126/science.1202529 · Cited by 4,244
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089
Inflammatory mechanisms linking obesity and metabolic disease
Saltiel, A. R., & Olefsky, J. M. (2017) · Journal of Clinical Investigation · doi:10.1172/jci92035 · Cited by 2,212 · cited 1×
“Systemic inflammation arises from infiltration and activation of macrophages in adipose tissue, leading to increased levels of inflammatory markers in serum and organs, such as liver, pancreas, and brain (Schmidt et al., 2015; Saltiel and Olefsky, 2017).”
Background
Microglia Shape Adult Hippocampal Neurogenesis through Apoptosis-Coupled Phagocytosis
Sierra, A., Encinas, J. M., Deudero, J. J. P., Chancey, J. H., Enikolopov, G., Overstreet-Wadiche, L. S., Tsirka, S. E., & Maletic-Savatic, M. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.08.014 · Cited by 1,622
Microglial interactions with synapses are modulated by visual experience
Tremblay, M.-È., Lowery, R. L., & Majewska, A. K. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000527 · Cited by 1,542
Control of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531
Adult hippocampal neurogenesis buffers stress responses and depressive behaviour
Snyder, J. S., Soumier, A., Brewer, M., Pickel, J., & Cameron, H. A. (2011) · Nature · doi:10.1038/nature10287 · Cited by 1,473
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Chung, W.-S., Clarke, L. E., Wang, G. X., Stafford, B. K., Sher, A., Chakraborty, C., Joung, J., Foo, L. C., Thompson, A., Chen, C., et al. (2013) · Nature · doi:10.1038/nature12776 · Cited by 1,377
Microglial Phagocytosis of Live Neurons
Brown, G. C., & Neher, J. J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3710 · Cited by 853
Minocycline selectively inhibits M1 polarization of microglia
Kobayashi, K., Imagama, S., Ohgomori, T., Hirano, K., Uchimura, K., Sakamoto, K., Hirakawa, A., Takeuchi, H., Suzumura, A., Ishiguro, N., et al. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.54 · Cited by 742
Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders
Profenno, L. A., Porsteinsson, A. P., & Faraone, S. V. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.02.013 · Cited by 718
Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function.
Valdearcos, M., Robblee, M. M., Benjamin, D. I., Nomura, D. K., Xu, A. W., & Koliwad, S. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.11.018 · Cited by 629
CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models
Lee, S., Varvel, N. H., Konerth, M. E., Xu, G., Cardona, A. E., Ransohoff, R. M., & Lamb, B. T. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.100265 · Cited by 522 · cited 1×
“…evidence as to whether Cx3cr1 deficiency increases or reduces microglial activation under neuroinflammatory conditions (Cardona et al., 2006; Lee et al., 2010; Lauro et al., 2015), although our data suggest that Cx3cr1 deficiency is protective against obesity-associated microglial…”
Background
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Adult neurogenesis: bridging the gap between mice and humans
Jessberger, S., & Gage, F. H. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.07.003 · Cited by 116

Flagged first, then by citations

Research works printed but not linked: 65

10.1126/science.1227901 · DOI · Paper page
10.1002/(SICI)1097-4547(19991001)58:1<33::AID-JNR5>3.0.CO;2-M · DOI
10.1016/j.bbr.2009.06.005 · DOI · Paper page
10.1242/dmm.006239 · DOI
10.1016/0092-8674(95)90010-1 · DOI
10.1523/JNEUROSCI.6413-10.2011 · DOI
10.1111/j.1467-789X.2008.00473.x · DOI · Paper page
10.1073/pnas.1511593112 · DOI · Paper page
10.1212/01.wnl.0000238082.13860.50 · DOI · Paper page
10.1038/nature10907 · DOI · Paper page
10.1016/j.neuron.2015.01.014 · DOI
10.1089/neu.1998.15.1037 · DOI
Franklin KB , Paxinos G (2008) The mouse brain in stereotaxic coordinates. New York: Elsevier Science.
10.1016/j.physbeh.2010.06.003 · DOI
10.1038/laban1005-39 · DOI
10.1016/j.comppsych.2006.05.001 · DOI · Paper page
10.1016/S0197-0186(03)00146-3 · DOI
10.1016/j.bbi.2015.08.023 · DOI
10.1073/pnas.95.18.10896 · DOI · Paper page
10.1016/j.nlm.2012.04.005 · DOI
10.1126/science.280.5368.1371 · DOI
10.1093/cercor/bhs151 · DOI
10.1038/oby.2009.273 · DOI · Paper page
10.1016/j.nlm.2015.03.003 · DOI
10.1128/MCB.20.11.4106-4114.2000 · DOI · Paper page
10.1186/1756-6606-4-27 · DOI
10.1111/nyas.12805 · DOI
10.1002/cne.22317 · DOI
10.1038/nri.2017.125 · DOI · Paper page
10.1038/oby.2008.296 · DOI
10.1161/01.STR.0000251791.64910.cd · DOI
10.1093/qjmed/hcl085 · DOI · Paper page
10.1016/j.bbi.2015.07.024 · DOI
10.1093/brain/awn109 · DOI · Paper page
10.1038/nprot.2006.258 · DOI
10.1016/j.tics.2015.01.001 · DOI · Paper page
10.2174/187152709788680689 · DOI
10.1002/glia.20207 · DOI · Paper page
10.1016/j.cell.2008.04.037 · DOI · Paper page
10.1523/JNEUROSCI.2042-13.2013 · DOI
10.1001/archneurol.2010.191 · DOI
10.1002/hbm.20870 · DOI
10.1073/pnas.93.25.14833 · DOI
10.1007/s10571-011-9791-1 · DOI
10.1523/JNEUROSCI.3667-11.2011 · DOI · Paper page
10.1371/journal.pone.0121971 · DOI · Paper page
10.1002/glia.20338 · DOI
10.1186/s40478-016-0374-8 · DOI
10.1371/journal.pone.0138317 · DOI
10.1523/JNEUROSCI.1619-13.2014 · DOI
10.4103/1673-5374.206633 · DOI
10.1111/j.1467-789X.2011.00920.x · DOI
10.1016/j.bbr.2011.06.024 · DOI
10.1172/JCI59660 · DOI · Paper page
10.1523/JNEUROSCI.21-08-02580.2001 · DOI · Paper page
10.1016/j.nlm.2013.06.012 · DOI
10.1007/978-1-61779-430-8_27 · DOI
10.1038/nm.4154 · DOI
10.1186/1471-2377-5-23 · DOI
10.1523/JNEUROSCI.3688-11.2011 · DOI
10.4103/1673-5374.156979 · DOI
Yagle, 2005, Evaluation of 18F-annexin V as a PET imaging agent in an animal model of apoptosis, J Nucl Med, 46, 658
10.1016/j.neuron.2011.07.024 · DOI · Paper page
10.1146/annurev.neuro.24.1.1071 · DOI · Paper page
10.2147/NDT.S73836 · DOI

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Zhang, D., Li, S., Hou, L., Jing, L., Ruan, Z., Peng, B., Zhang, X., Hong, J.-S., Zhao, J., & Wang, Q. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02065-z · Cited by 187
Association of anthropometry and weight change with risk of dementia and its major subtypes: a meta-analysis consisting 2.8 million adults with 57 294 cases of dementia
Lee, C. M., Woodward, M., Batty, G. D., Beiser, A. S., Bell, S., Berr, C., Bjertness, E., Chalmers, J., Clarke, R., Dartigues, J., et al. (2020) · Obesity Reviews · doi:10.1111/obr.12989 · Cited by 142
Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain
Kiss, T., Nyúl-Tóth, Á., DelFavero, J., Balasubramanian, P., Tarantini, S., Faakye, J., Gulej, R., Ahire, C., Ungvari, A., Yabluchanskiy, A., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00521-7 · Cited by 66
Dysregulated resting state functional connectivity and obesity: A systematic review
Syan, S. K., McIntyre-Wood, C., Minuzzi, L., Hall, G., McCabe, R. E., & MacKillop, J. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.08.019 · Cited by 66
Direct and indirect effects of lipids on microglia function
Leyrolle, Q., Layé, S., & Nadjar, A. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134348 · Cited by 50
Atypical perineuronal nets in the CA2 region interfere with social memory in a mouse model of social dysfunction
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Yohn, S. E., Galbraith, J., Calipari, E. S., & Conn, P. J. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00601 · Cited by 36
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Authors: Cope, E. C., LaMarca, E. A., Monari, P. K., Olson, L. B., Martinez, S., Zych, A. D., Katchur, N. J., & Gould, E.
ORCID: Cope, Elise C.
Monari, Patrick K.
Katchur, Nicole J.
Gould, Elizabeth
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2018-09-10
Volume: 38
Issue: 41
Pages: 8889-8904
ISSN: 0270-6474
1529-2401
DOI: 10.1523/jneurosci.0789-18.2018
Cited by: 219
References: 16
Language: en
Licence: creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 212 d)

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Microglia Play an Active Role in Obesity-Associated Cognitive Decline

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