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Gamma frequency entrainment attenuates amyloid load and modifies microglia
Open accessAbstract
Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1-40 and Aβ 1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ 1-40 and Aβ 1-42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.
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“By genetically engineering these proteins into target neurons and controlling the light around them, these neurons can be activated or inhibited, which is particularly important for sensory and motor recovery and rehabilitation.[555]”
From Flexible Electronics and Devices as Human–Machine Interfaces for Medical Robotics (2022) · cites this paper as [555]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Optogenetic stimulation is based on opsins that are sensitive to light signals and only expressed in certain types of cells.”
From Flexible Electronics and Devices as Human–Machine Interfaces for Medical Robotics (2022) · cites this paper as [555]
The cited source says what the claim attributes to it.
In the citing paper
“Indeed, gamma frequency modulation was beneficial in models with amyloid and/or tau pathology54.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [54]
The cited source says what the claim attributes to it.
In the citing paper
“Indeed, gamma frequency modulation was found to be beneficial in models with either amyloid and/or tau pathology52”
From APOE3 - R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“our sample sizes are similar to those reported in previous publications.15,24,86”
From TERT activation targets DNA methylation and multiple aging hallmarks (2024) · cites this paper as [86]
In the citing paper
“Interestingly, entraining gamma oscillation at 40 Hz in 5xFAD mice induced amyloid reductions that were associated with an increase in microglial numbers and morphological changes such as soma enlargement and shortening of processes loaded with Aβ.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“Interestingly, entraining gamma oscillation at 40 Hz in 5xFAD mice induced amyloid reductions that were associated with an increase in microglial numbers and morphological changes such as soma enlargement and shortening of processes loaded with Aβ.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“Gamma oscillations arise from the activation of local circuits of excitatory and fast-spiking inhibitory neurons resonating at 20-50 Hz, and changes in gamma oscillation have been observed in neurological diseases (158).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“Gamma oscillations arise from the activation of local circuits of excitatory and fast-spiking inhibitory neurons resonating at 20-50 Hz, and changes in gamma oscillation have been observed in neurological diseases (158).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“Interestingly, entraining gamma oscillation at 40 Hz in 5xFAD mice induced amyloid reductions that were associated with an increase in microglial numbers and morphological changes such as soma enlargement and shortening of processes loaded with Aβ.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“Notably, levels of proinflammatory genes (Il1b, Il6, Cd11b) and antiinflammatory genes (Igf1) were not changed (158), suggesting that it is possible to use immunomodulation to polarize microglia toward a beneficial activation state that is characterized by increased phagocytic activity without the induction of sustained inflammatory responses.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“Notably, levels of proinflammatory genes (Il1b, Il6, Cd11b) and antiinflammatory genes (Igf1) were not changed (158), suggesting that it is possible to use immunomodulation to polarize microglia toward a beneficial activation state that is characterized by increased phagocytic activity without the induction of sustained inflammatory responses.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“RNA sequencing analysis showed an increase in phagocytic genes, such as Cd68, β 2 -microglobulin (B2m), Icam, and lysozyme 2 (Lyz2), and in the proliferation markers Csf1, Csf1r, and Csf2ra.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“RNA sequencing analysis showed an increase in phagocytic genes, such as Cd68, β 2 -microglobulin (B2m), Icam, and lysozyme 2 (Lyz2), and in the proliferation markers Csf1, Csf1r, and Csf2ra.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [158]
In the citing paper
“In mice, slow gamma frequency visual or audio input entrains neural firing to this frequency in the cortex and hippocampus and reduces Aβ pathology and microglial abnormalities [204, 205].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [204]
In the citing paper
“Transgenic mice with AD-like pathology were found to have reduced gamma power that, in one model, precedes cognitive impairment and amyloid plaque formation [21,22].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [21]
In the citing paper
“Interestingly, amyloid plaques were reduced when hippocampal PV-INs artificially produced gamma oscillations in optogenetics paradigms [21].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [21]
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Cites
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · cited 1×
“To understand the cellular and molecular mechanisms from our RNA-seq data, 14 of publicly available RNA-seq datasets 35 were processed for cell-type-specific analysis.”
Buzsáki, G. (2006) · doi:10.1093/acprof:oso/9780195301069.001.0001 · Cited by 4,873
Gray, C. M., König, P., Engel, A. K., & Singer, W. (1989) · Nature · doi:10.1038/338334a0 · Cited by 4,183
Host microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530
Theta oscillations in the hippocampus
Buzsáki, G. (2002) · Neuron · doi:10.1016/s0896-6273(02)00586-x · Cited by 3,332
Driving fast-spiking cells induces gamma rhythm and controls sensory responses
Cardin, J. A., Carlén, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., Tsai, L.-H., & Moore, C. I. (2009) · Nature · doi:10.1038/nature08002 · Cited by 2,603
Self-citationCoherent oscillations: A mechanism of feature linking in the visual cortex?
Eckhorn, R., Bauer, R., Jordan, W., Brosch, M., Kruse, W., Munk, M., & Reitboeck, H. J. (1988) · Biological Cybernetics · doi:10.1007/bf00202899 · Cited by 2,329
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208
Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks
Bartos, M., Vida, I., & Jonas, P. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2044 · Cited by 2,070
Structural and molecular interrogation of intact biological systems
Chung, K., Wallace, J., Kim, S.-Y., Kalyanasundaram, S., Andalman, A. S., Davidson, T. J., Mirzabekov, J. J., Zalocusky, K. A., Mattis, J., Denisin, A. K., et al. (2013) · Nature · doi:10.1038/nature12107 · Cited by 2,008
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
Reverse replay of behavioural sequences in hippocampal place cells during the awake state
Foster, D. J., & Wilson, M. A. (2006) · Nature · doi:10.1038/nature04587 · Cited by 1,727
Palop, J. J., Chin, J., Roberson, E. D., Wang, J., Thwin, M. T., Bien-Ly, N., Yoo, J., Ho, K. O., Yu, G.-Q., Kreitzer, A., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.07.025 · Cited by 1,653
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575
Frequency of gamma oscillations routes flow of information in the hippocampus
Colgin, L. L., Denninger, T., Fyhn, M., Hafting, T., Bonnevie, T., Jensen, O. B., Moser, M., & Moser, E. I. (2009) · Nature · doi:10.1038/nature08573 · Cited by 1,489
Gosselin, D., Link, V. M., Romanoski, C. E., Fonseca, G. J., Eichenfield, D. Z., Spann, N. J., Stender, J. D., Chun, H. B., Garner, H., Geissmann, F., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.023 · Cited by 1,307
Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages
Huang, S. C., Everts, B., Ivanova, Y., O’Sullivan, D., Nascimento, M., Smith, A. M., Beatty, W. L., Love-Gregory, L. D., Lam, W. Y., O’Neill, C. M., et al. (2014) · Nature Immunology · doi:10.1038/ni.2956 · Cited by 1,256
Verret, L., Mann, E. O., Hang, G. B., Barth, A. M. I., Cobos, I., Ho, K., Devidze, N., Masliah, E., Kreitzer, A. C., Mody, I., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.046 · Cited by 1,216
Fries, P., Nikolić, D., & Singer, W. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.05.005 · Cited by 1,044
Hippocampal replay in the awake state: a potential substrate for memory consolidation and retrieval
Carr, M. F., Jadhav, S. P., & Frank, L. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2732 · Cited by 958
Neuronal activity regulates the regional vulnerability to amyloid-β deposition
Bero, A. W., Yan, P., Roh, J. H., Cirrito, J. R., Stewart, F. R., Raichle, M. E., Lee, J.-M., & Holtzman, D. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2801 · Cited by 880
Intracellular dynamics of hippocampal place cells during virtual navigation
Harvey, C. D., Collman, F., Dombeck, D. A., & Tank, D. W. (2009) · Nature · doi:10.1038/nature08499 · Cited by 875
Spike sorting for large, dense electrode arrays
Rossant, C., Kadir, S., Goodman, D. F. M., Schulman, J., Hunter, M. L. D., Saleem, A. B., Grosmark, A., Belluscio, M., Denfield, G. H., Ecker, A. S., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4268 · Cited by 800
Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gomez-Isla, T., Hyman, B. T., & Nixon, R. A. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64538-5 · Cited by 776
Chiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.018 · Cited by 651
Colony-stimulating factor-1 in immunity and inflammation
Chitu, V., & Stanley, E. R. (2006) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.11.006 · Cited by 635
Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease
Gjoneska, E., Pfenning, A. R., Mathys, H., Quon, G., Kundaje, A., Tsai, L.-H., & Kellis, M. (2015) · Nature · doi:10.1038/nature14252 · Cited by 576
Self-citationThe road to restoring neural circuits for the treatment of Alzheimer's disease
Canter, R. G., Penney, J., & Tsai, L.-H. (2016) · Nature · doi:10.1038/nature20412 · Cited by 565
Self-citationHippocampal network patterns of activity in the mouse
Buzsáki, G., Buhl, D. L., Harris, K. D., Csicsvari, J., Czéh, B., & Morozov, A. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00669-3 · Cited by 486
Multisensory Control of Hippocampal Spatiotemporal Selectivity
Ravassard, P., Kees, A. L., Willers, B., Ho, D. G., Aharoni, D. B., Cushman, J. D., Aghajan, Z. M., & Mehta, M. R. (2013) · Science · doi:10.1126/science.1232655 · Cited by 385
Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors
Crotti, A., Benner, C., Kerman, B. E., Gosselin, D., Lagier-Tourenne, C., Zuccato, C., Cattaneo, E., Gage, F. H., Cleveland, D. W., & Glass, C. K. (2014) · Nature Neuroscience · doi:10.1038/nn.3668 · Cited by 333
Engagement of Neural Circuits Underlying 2D Spatial Navigation in a Rodent Virtual Reality System
Aronov, D., & Tank, D. W. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.042 · Cited by 325
Stam, C. J., van Walsum, A. V. C., Pijnenburg, Y. A. L., Berendse, H. W., de Munck, J. C., Scheltens, P., & van Dijk, B. W. (2002) · Journal of Clinical Neurophysiology · doi:10.1097/00004691-200212000-00010 · Cited by 302
Transient Slow Gamma Synchrony Underlies Hippocampal Memory Replay
Carr, M. F., Karlsson, M. P., & Frank, L. M. (2012) · Neuron · doi:10.1016/j.neuron.2012.06.014 · Cited by 265
Das, U., Scott, D. A., Ganguly, A., Koo, E. H., Tang, Y. P., & Roy, S. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.035 · Cited by 259
The Role of APP Processing and Trafficking Pathways in the Formation of Amyloid β‐Proteina
SELKOE, D. J., YAMAZAKI, T., CITRON, M., PODLISNY, M. B., KOO, E. H., TEPLOW, D. B., & HAASS, C. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb34401.x · Cited by 205
Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair
Yu, H., Su, Y., Shin, J., Zhong, C., Guo, J. U., Weng, Y., Gao, F., Geschwind, D. H., Coppola, G., Ming, G., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4008 · Cited by 199
Self-citationGillespie, A. K., Jones, E. A., Lin, Y.-H., Karlsson, M. P., Kay, K., Yoon, S. Y., Tong, L. M., Nova, P., Carr, J. S., Frank, L. M., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.009 · Cited by 187
Helwig, M., Hoshino, A., Berridge, C., Lee, S., Lorenzen, N., Otzen, D. E., Eriksen, J. L., & Lindberg, I. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.417071 · Cited by 59
Sex differences in the response to GABA antagonists depend on the route of drug administration
Peričić, D., & Bujas, M. (1997) · Experimental Brain Research · doi:10.1007/pl00005681 · Cited by 21
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Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125
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Metadata
- Authors
- Iaccarino, H. F., Singer, A. C., Martorell, A. J., Rudenko, A., Gao, F., Gillingham, T. Z., Mathys, H., Seo, J., Kritskiy, O., Abdurrob, F., Adaikkan, C., Canter, R. G., Rueda, R., Brown, E. N., Boyden, E. S., & Tsai, L.-H.
- Affiliations
- McGovern Institute for Brain Research (US)
- Massachusetts Institute of Technology (US)
- Massachusetts General Hospital (US)
- Broad Institute (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Nature
- Published
- 2016-12-07
- Volume
- 540
- Issue
- 7632
- Pages
- 230-235
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5656389
- OpenAlex
- W2560234750
- Cited by
- 1,328
- References
- 41
- Citations by year
- 2026: 169 · 2025: 191 · 2024: 172 · 2023: 160 · 2022: 147 · 2021: 150 · 2020: 131 · 2019: 85 · 2018: 76 · 2017: 42 · 2016: 2
- FWCI
- 54.95
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- PMC
- Funders
- National Institute on Aging (RF1AG047661)
- National Eye Institute (R01EY023173)
- National Institute of General Medical Sciences (R01GM104948)
- National Institute of Neurological Disorders and Stroke (DP1NS087724)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- gamma oscillations, Alzheimer's disease, amyloid-beta, microglia, parvalbumin interneurons, optogenetics, amyloid plaques, 5xFAD mice, APP/PS1 mice, visual cortex, neurodegeneration
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Disease Models, Animal, Female, Interneurons, Light, Male, Parvalbumins, Peptide Fragments, Visual Cortex, Amyloid beta-Peptides, Microglia, Cell Shape, Mice, CA1 Region, Hippocampal, Plaque, Amyloid, Transcriptome, Optogenetics, Gamma Rhythm
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