The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

Tseng, Jui-Heng; Xie, Ling; Song, Sheng; Xie, Youmei; Allen, Lauren; Ajit, Deepa; Hong, Jau-Shyong; Chen, Xian; Meeker, Rick B.; Cohen, Todd J.

doi:10.1016/j.celrep.2017.07.082

Cited by 96Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

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Tseng, Jui-Heng, Xie, Ling, Song, Sheng, Xie, Youmei, Allen, Lauren, Ajit, Deepa, Hong, Jau-Shyong, Chen, Xian +2 more·2017·Cell Reports

DOI 10.1016/j.celrep.2017.07.082PMC PMC5578720

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Abstract

The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.

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Increased expression of HDAC6 decreases Tau acetylation, a key factor contributing to the formation of Tau aggregates.
“Increased expression of HDAC6 decreases Tau acetylation [40], which is a key factor contributing to the formation of Tau aggregates [39, 49].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [49]
The Discussion reports that inhibiting HDAC6 mildly increased tau acetylation, which supports a role for HDAC6 activity in regulating it. The paper does not show that increased HDAC6 expression decreases tau acetylation; it also reports increased acetylated tau in HDAC6-containing neuritic beads. Citation [40] is attached to the HDAC6 clause, not the separate aggregation claim. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Under neuroinflammatory stress, deletion or inhibition of HDAC6 suppresses mislocalization and neuritic aggregation of tau through a MMP-9-mediated mechanism.
“However, other studies found that under neuroinflammatory stress, deletion or inhibition of HDAC6 suppresses mislocalization and neuritic aggregation of tau through a matrix metalloproteinase (MMP-9)-mediated mechanism [182].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [182]

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Takeuchi H Mizuno T Zhang G Wang J Kawanokuchi J Kuno R Suzumura A 2005 Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport The Journal of biological chemistry 280 10444 10454 15640150

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The tubulin code and its role in controlling microtubule properties and functions
Janke, C., & Magiera, M. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0214-3 · Cited by 956 · see citing works
Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
Chen, Y., & Yu, Y. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02853-3 · Cited by 516 · see citing works
“However, other studies found that under neuroinflammatory stress, deletion or inhibition of HDAC6 suppresses mislocalization and neuritic aggregation of tau through a matrix metalloproteinase (MMP-9)-mediated mechanism [182].”
Background
The complexity of tau in Alzheimer’s disease
Naseri, N. N., Wang, H., Guo, J. D., Sharma, M., & Luo, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.022 · Cited by 374 · see citing works
Intersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197 · see citing works
Doxorubicin and cisplatin induced cognitive impairment: The possible mechanisms and interventions
Ongnok, B., Chattipakorn, N., & Chattipakorn, S. C. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113118 · Cited by 145 · see citing works
New Insights Into Drug Discovery Targeting Tau Protein
Soeda, Y., & Takashima, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.590896 · Cited by 133 · see citing works
Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models
Choi, H., Kim, H. J., Yang, J., Chae, S., Lee, W., Chung, S., Kim, J., Choi, H., Song, H., Lee, C. K., et al. (2019) · Aging Cell · doi:10.1111/acel.13081 · Cited by 122 · see citing works
Ageing – Oxidative stress, PTMs and disease
Ebert, T., Ngoc, T. U., Schurgers, L. J., Stenvinkel, P., & Shiels, P. G. (2022) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2022.101099 · Cited by 121 · see citing works
An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline
Trzeciakiewicz, H., Ajit, D., Tseng, J.-H., Chen, Y., Ajit, A., Tabassum, Z., Lobrovich, R., Peterson, C., Riddick, N. V., Itano, M. S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19317-4 · Cited by 102 · see citing works
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Molecular and functional signatures in a novel Alzheimer’s disease mouse model assessed by quantitative proteomics
Kim, D. K., Park, J., Han, D., Yang, J., Kim, A., Woo, J., Kim, Y., & Mook-Jung, I. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0234-4 · Cited by 95 · see citing works
The Roles of Microtubules and Membrane Tension in Axonal Beading, Retraction, and Atrophy
Datar, A., Ameeramja, J., Bhat, A., Srivastava, R., Mishra, A. K., Bernal, R., Prost, J., Callan-Jones, A., & Pullarkat, P. A. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.07.046 · Cited by 88 · see citing works
Inhibition of Histone Deacetylase 6 (HDAC6) as a therapeutic strategy for Alzheimer's disease: A review (2010–2020)
Li, Y., Sang, S., Ren, W., Pei, Y., Bian, Y., Chen, Y., & Sun, H. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113874 · Cited by 77 · see citing works
Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment
Ma, J., Huo, X., Jarpe, M. B., Kavelaars, A., & Heijnen, C. J. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0604-3 · Cited by 73 · see citing works
Tubulin Post-Translational Modifications: The Elusive Roles of Acetylation
Carmona, B., Marinho, H. S., Matos, C. L., Nolasco, S., & Soares, H. (2023) · Biology · doi:10.3390/biology12040561 · Cited by 58 · see citing works
Targeting Aggrephagy for the Treatment of Alzheimer’s Disease
Malampati, S., Song, J., Tong, B. C., Nalluri, A., Yang, C., Wang, Z., Sreenivasmurthy, S. G., Zhu, Z., Liu, J., Su, C.-F., et al. (2020) · Cells · doi:10.3390/cells9020311 · Cited by 58 · see citing works
Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment
Chiang, A. C. A., Huo, X., Kavelaars, A., & Heijnen, C. J. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.04.005 · Cited by 57 · see citing works
Classical HDACs in the regulation of neuroinflammation
Dai, Y., Wei, T.-F., Shen, Z., Bei, Y., Lin, H., & Dai, H. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105182 · Cited by 55 · see citing works
Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease
Tseng, H.-J., Lin, M.-H., Shiao, Y., Yang, Y.-C., Chu, J.-C., Chen, C.-Y., Chen, Y.-Y., Lin, T. E., Su, C.-J., Pan, S., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112193 · Cited by 55 · see citing works
Dephosphorylated rather than hyperphosphorylated Tau triggers a pro-inflammatory profile in microglia through the p38 MAPK pathway
Perea, J. R., Ávila, J., & Bolós, M. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.08.007 · Cited by 54 · see citing works
Histone deacetylase-6 modulates Tau function in Alzheimer's disease
Qureshi, T., & Chinnathambi, S. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2022.119275 · Cited by 49 · see citing works
MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells
Chen, M.-C., Lin, Y., Liao, Y.-H., Liou, J., & Chen, C. (2019) · Cancers · doi:10.3390/cancers11101617 · Cited by 41 · see citing works
Gedunin Inhibits Oligomeric Aβ1–42-Induced Microglia Activation Via Modulation of Nrf2-NF-κB Signaling
Tom, S., Rane, A., Katewa, A., Chamoli, M., Matsumoto, R. R., Andersen, J. K., & Chinta, S. J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1636-9 · Cited by 39 · see citing works
HDAC6 Modulates Signaling Pathways Relevant to Synaptic Biology and Neuronal Differentiation in Human Stem Cell-Derived Neurons
Iaconelli, J., Xuan, L. L., & Karmacharya, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071605 · Cited by 37 · see citing works
TLR4-TAK1-p38 MAPK pathway and HDAC6 regulate the expression of sigma-1 receptors in rat primary cultured microglia
Iwamoto, M., Nakamura, Y., Takemura, M., Hisaoka‐Nakashima, K., & Morioka, N. (2020) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2020.06.007 · Cited by 36 · see citing works
Cortactin deacetylation by HDAC6 and SIRT2 regulates neuronal migration and dendrite morphogenesis during cerebral cortex development
Kim, J.-Y., Hwang, H.-G., Lee, J., Kim, J., & Kim, J. (2020) · Molecular Brain · doi:10.1186/s13041-020-00644-y · Cited by 34 · see citing works
Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer’s disease
Hernández, J. M., Parato, J., Sharma, A., Soleilhac, J.-M., Qu, X., Tein, E., Sproul, A. A., Andrieux, A., Goldberg, Y., Moutin, M., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.926914 · Cited by 32 · see citing works
A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation
Ajit, D., Trzeciakiewicz, H., Tseng, J., Wander, C. M., Chen, Y., Ajit, A., King, D. P., & Cohen, T. J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009674 · Cited by 31 · see citing works
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Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer’s disease
He, F., Ran, Y., Li, X., Wang, D., Zhang, Q., Lv, J., Yu, C., Qu, Y., Zhang, X., Xu, A., et al. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.104109 · Cited by 31 · see citing works
Structure-Based Drug Designing Recommends HDAC6 Inhibitors To Attenuate Microtubule-Associated Tau-Pathogenesis
Zeb, A., Park, C., Rampogu, S. D., Son, M., Lee, G., & Lee, K. W. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00405 · Cited by 30 · see citing works
The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging
Wander, C. M., Tseng, J., Song, S., Housseiny, H. A., Tart, D. S., Ajit, A., Shih, Y. I., Lobrovich, R., Song, J., Meeker, R. B., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101255 · Cited by 30 · see citing works
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The Accumulation of Tau in Postsynaptic Structures—A Common Feature in Multiple Neurodegenerative Diseases?
Teravskis, P. J., Ashe, K., & Liao, D. (2020) · The Neuroscientist · doi:10.1177/1073858420916696 · Cited by 21 · see citing works
Inhibition of HDAC6 by Tubastatin A reduces chondrocyte oxidative stress in chondrocytes and ameliorates mouse osteoarthritis by activating autophagy
Shen, Z., Ji, K., Cai, Z., Huang, C., He, X., Xu, H., & Chen, G. (2021) · Aging · doi:10.18632/aging.202736 · Cited by 27 · see citing works
A Distinct Tau Code Controlled by HDAC6 is Linked to Tau Pathogenesis and the Neuronal Stress Response
Tseng, J., Ajit, A., Tabassum, Z., Patel, N., Tian, X., Chen, Y., Prevatte, A. W., Ling, K., Rigo, F., Meeker, R. B., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2021.109037 · Cited by 26 · see citing works
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Potential Therapeutic Role of HDAC Inhibitors in FUS-ALS
Tejido, C., Pakravan, D., & Bosch, L. V. D. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.686995 · Cited by 26 · see citing works
Histone Deacetylases (HDACs) Roles in Inflammation-mediated Diseases; Current Knowledge
Jasim, S. A., Altalbawy, F. M. A., Abohassan, M., Oghenemaro, E. F., Bishoyi, A. K., Singh, R. P., Kaur, P., Sivaprasad, G. V., Mohammed, J. S., & Hulail, H. M. (2024) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-024-01587-0 · Cited by 23 · see citing works
Curcumin prevents neurodegeneration by blocking HDAC6–NLRP3 pathway-dependent neuroinflammation in Parkinson’s disease
Cai, Z., Liang, C., Huang, K.-L., Luo, J., Lu, R., Lai, Y., Zheng, D., Lin, Z., Zhong, J., Dai, J., et al. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113928 · Cited by 22 · see citing works
Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models
Sanz‐Alcázar, A., Britti, E., Delaspre, F., Medina‐Carbonero, M., Pazos-Gil, M., Tamarit, J., Ros, J., & Cabiscol, E. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-05064-4 · Cited by 21 · see citing works
Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau
Jeong, H., Shin, S., Lee, J., Lee, S. H., Baik, J., Lim, S., & Kim, Y. K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174283 · Cited by 22 · see citing works
Synthesis and biological evaluation of selective histone deacetylase 6 inhibitors as multifunctional agents against Alzheimer's disease
Wang, X.-X., Xie, F., Jia, C.-C., Yan, N., Zeng, Y.-L., Wu, J.-D., & Liu, Z.-P. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113821 · Cited by 23 · see citing works
DiLeu Isobaric Labeling Coupled with Limited Proteolysis Mass Spectrometry for High-Throughput Profiling of Protein Structural Changes in Alzheimer’s Disease
Lu, H., Wang, B., Liu, Y., Wang, D., Fields, L. G., Zhang, H., Li, M., Shi, X., Zetterberg, H., & Li, L. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.2c05731 · Cited by 21 · see citing works
Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems
Quiroga, I. Y., Cruikshank, A. E., Reed, K. S. M., Bond, M. L., Evangelista, B., Tseng, J., Ragusa, J. V., Meeker, R. B., Won, H., Cohen, S., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02459-1 · Cited by 19 · see citing works
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Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity
Opland, C. K., Bryan, M. R., Harris, B., McGillion-Moore, J., Tian, X., Chen, Y., Itano, M. S., Diering, G. H., Meeker, R. B., & Cohen, T. J. (2023) · iScience · doi:10.1016/j.isci.2023.106905 · Cited by 21 · see citing works
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Modeling axonal regeneration by changing cytoskeletal dynamics in stem cell-derived motor nerve organoids
Seo, W. M., Yoon, J.-Y., Lee, J., Lee, Y., Lee, H.-J., Geum, D., Sun, W., & Song, M. (2022) · Scientific Reports · doi:10.1038/s41598-022-05645-6 · Cited by 18 · see citing works
Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease
Wander, C. M., Tsujimoto, T. H. M., Ervin, J. F., Wang, C., Maranto, S. M., Bhat, V., Dallmeier, J., Wang, S. J., Lin, F., Scott, W. K., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01409-5 · Cited by 18 · see citing works
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Modeling neurotoxin-induced neuroinflammation with chemotherapy
Tolba, M. F., Sedky, N. K., Ali, M. A., & Abdollah, M. R. A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-89833-1.00049-5 · Cited by 17 · see citing works
Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice
Xie, Y., Seawell, J. A., Boesch, E., Allen, L. D., Suchy, A., Longo, F. M., & Meeker, R. B. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113489 · Cited by 16 · see citing works
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Design of Multi-Target drugs of HDACs and other Anti-Alzheimer related Targets: Current strategies and future prospects in Alzheimer’s diseases therapy
Soltan, O. M., Abdelrahman, K. S., Bass, A. K. A., Takizawa, K., Narumi, A., & Konno, H. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107651 · Cited by 14 · see citing works
Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion
Corey, D. A., Rymut, S. M., & Kelley, T. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-73298-4 · Cited by 13 · see citing works
Class I and II histone deacetylase expression is not altered in human amyotrophic lateral sclerosis: Neuropathological and positron emission tomography molecular neuroimaging evidence
Dios, A. M., Babu, S., Granucci, E. J., Mueller, K. A., Mills, A. N., Alshikho, M. J., Zürcher, N. R., Cernasov, P., Gilbert, T. M., Glass, J. D., et al. (2019) · Muscle & Nerve · doi:10.1002/mus.26620 · Cited by 12 · see citing works
Neuronal loss and inflammation preceding fibrillary tau pathology in a rat model with early human-like tauopathy
Emmerson, J. T., Malcolm, J. C., Carmo, S. D., Nguyen, P., Breuillaud, L., Martínez-Trujillo, J., & Cuello, A. C. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106317 · Cited by 11 · see citing works
Applications and Challenges of Machine Learning Methods in Alzheimer's Disease Multi-Source Data Analysis
Li, X., Qiu, Y., Zhou, J. H., & Xie, Z. (2021) · Current Genomics · doi:10.2174/1389202923666211216163049 · Cited by 11 · see citing works
Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons
Saleem, K., Xiao, Z., Zhu, B., Ren, Y., Yan, Z., & Feng, J. (2026) · Molecular Psychiatry · doi:10.1038/s41380-025-03225-4 · Cited by 10 · see citing works
ALS-associated TDP-43 aggregates drive innate and adaptive immune cell activation
Evangelista, B., Ragusa, J. V., Pellegrino, K., Wu, Y., Quiroga, I. Y., Cahalan, S. R., Arooji, O. K., Madren, J. A., Schroeter, S., Cozzarin, J., et al. (2025) · iScience · doi:10.1016/j.isci.2025.112648 · Cited by 10 · see citing works
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Emerging roles for tubulin PTMs in neuronal function and neurodegenerative disease
Teoh, J. J., & Bartolini, F. (2025) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2025.102971 · Cited by 10 · see citing works
Histone deacetylase’s regulates Tau function in Alzheimer’s disease
Chinnathambi, S. (2024) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2024.09.008 · Cited by 9 · see citing works
Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice
Zamorano, M., Alexander, J. F., Catania, D., Dharmaraj, S., Kavelaars, A., & Heijnen, C. J. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00328-w · Cited by 9 · see citing works
Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6
Osko, J. D., & Christianson, D. W. (2020) · Acta Crystallographica Section F Structural Biology Communications · doi:10.1107/s2053230x20010250 · Cited by 9 · see citing works
Decoding tau acetylation in Alzheimer’s disease and tauopathies: from site-specific mechanisms to therapeutic horizons
Oh, Y. R., & Shin, M. (2025) · BMB Reports · doi:10.5483/bmbrep.2025-0077 · Cited by 9 · see citing works
Development and characterization of novel anti-acetylated tau monoclonal antibodies to probe pathogenic tau species in Alzheimer’s disease
Bryan, M. R., Tian, X., Tseng, J., Evangelista, B., Ragusa, J. V., Bryan, A. F., Trotman, W., Irwin, D. J., & Cohen, T. J. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01865-1 · Cited by 8 · see citing works
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Therapeutic potential of dual HDAC6/SIRT2 inhibition in Alzheimer's disease
Wang, X., Li, C., Chen, L., He, B., & Li, Y. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117733 · Cited by 8 · see citing works
Beyond Neuroinflammation: Microglia at the Crossroads of Amyloid, Tau, and Neurodegeneration in Alzheimer’s Disease
Ebrahimi, R., Bordbar, S., Azad, G., Davoody, S., Mahmoudi, M., & Esmaeilpour, K. (2025) · Neurological Sciences · doi:10.1007/s10072-025-08403-4 · Cited by 8 · see citing works
Dysfunction of the noradrenergic system drives inflammation, α-synucleinopathy, and neuronal loss in mouse colon
Song, S., Tu, D., Meng, C., Liu, J., Wilson, B. C., Wang, Q., Shih, Y. I., Gao, H., & Hong, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1083513 · Cited by 6 · see citing works
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Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities
Chu, J.-C., Tseng, H.-J., Lee, S., Hsu, K., Hsin, L., Liang, R.-H., Lin, T. E., Gao, N.-C., Chen, L., Lu, W.-H., et al. (2023) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2023.2212326 · Cited by 5 · see citing works
Chemobrain: An accelerated aging process linking adenosine A2A receptor signaling in cancer survivors
Oliveros, A., Poleschuk, M., Cole, P. D., Boison, D., & Jang, M. (2023) · International review of neurobiology · doi:10.1016/bs.irn.2023.08.003 · Cited by 5 · see citing works
Antisense Oligonucleotide-Mediated Reduction of HDAC6 Does Not Reduce Tau Pathology in P301S Tau Transgenic Mice
Valencia, A., Bieber, V. L. R., Bajrami, B., Marsh, G., Hamann, S., Wei, R., Ling, K., Rigo, F., Arnold, H. M., Golonzhka, O., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.624051 · Cited by 5 · see citing works
Moderate pyridoxal phosphate deficiency enhances neuronal excitability and promotes calcium dysregulation
Girgis, V., Tharington, A., Trivett, J., Fitting, S., Meeker, R. B., & Rubiños, C. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1621349 · Cited by 4 · see citing works
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Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases
Aleksandrova, Y. R., & Неганова, М. Е. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914766 · Cited by 4 · see citing works
Improved neurocognitive performance in FIV infected cats following treatment with the p75 neurotrophin receptor ligand LM11A-31
Fogle, J. E., Hudson, L. C., Thomson, A., Sherman, B. L., Gruen, M. E., Lascelles, B. D. X., Colby, B., Clary, G., Longo, F. M., & Meeker, R. B. (2021) · Journal of NeuroVirology · doi:10.1007/s13365-021-00956-2 · Cited by 4 · see citing works
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Role of NRP1/HDAC4/CREB/RIPK1 Axis in SARS‐CoV2 S1 Spike Subunit‐Induced Neuronal Toxicity
Sanguigno, L., Guida, N., Cammarota, M., Ruggiero, S., Serani, A., Galasso, F., Pizzorusso, V., Boscia, F., & Formisano, L. (2025) · FASEB BioAdvances · doi:10.1096/fba.2025-00005 · Cited by 3 · see citing works
ACY1215 Exerts Anti-inflammatory Effects by Inhibition of NF-κB and STAT3 Signaling Pathway to Repair Spinal Cord Injury
Dai, C., Wang, X., Liu, R., Gao, W., Zhang, H., Yin, Z., & Ding, Z. (2024) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b23-00603 · Cited by 3 · see citing works
In silico and In vivo protective effect of biochanin-A mitigating doxorubicin- induced cognitive deficits and neuroinflammation: Insights to the role of p-Tau and miR-132
Hussein, S., Tolba, M. F., Michel, H. E., Albohy, A., & Azab, S. S. (2025) · NeuroToxicology · doi:10.1016/j.neuro.2025.01.003 · Cited by 3 · see citing works
HDAC6 Deficiency Has Moderate Effects on Behaviors and Parkinson’s Disease Pathology in Mice
Zhao, J., He, Y., Duan, Y., Ma, Y., Dong, H., Zhang, X., Fang, R., Zhang, Y., Yu, M., & Huang, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129975 · Cited by 3 · see citing works
The emerging nontraditional roles for tau in the brain
Tseng, J., & Cohen, T. J. (2023) · Cytoskeleton · doi:10.1002/cm.21811 · Cited by 2 · see citing works
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Deficient Mitochondrial Respiration Impairs Sirtuin Activity in Dorsal Root Ganglia in Friedreich Ataxia Mouse and Cell ModelsPreprint
Sanz‐Alcázar, A., Britti, E., Delaspre, F., Medina‐Carbonero, M., Pazos-Gil, M., Tamarit, J., Ros, J., & Cabiscol, E. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.01.526688 · Cited by 2 · see citing works
Extracellular HDAC6 ZnF UBP domain enhances podosome-mediated neuronal migrationPreprint
Qureshi, T., Desale, S. E., Sonawane, S. K., Balmik, A. A., Chidambaram, H., & Chinnathambi, S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.04.626746 · Cited by 2 · see citing works
Mechanisms of Aggresome Biogenesis Ubiquitination, Transport, & MaintenancePreprint
Keefe, A. (2018) · Preprints.org · doi:10.20944/preprints201812.0332.v1 · Cited by 1 · see citing works
Epigenetic Dysregulation in the Basocortical Cholinergic Projection System During the Progression of Alzheimer's Disease
Mahady, L. J. (2018)
The Role of Tau in Network Dysfunction and Alzheimer's Disease Pathogenesis
Dombroski, A. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/hepv-3645
Mechanisms of Aggresome Biogenesis: Ubiquitination, Transport, & MaintenancePreprint
Keefe, A. (2019) · Preprints.org · doi:10.20944/preprints201812.0332.v2
Als-Associated Tdp-43 Aggregates Drive Innate and Adaptive Immune Cell ActivationPreprint
Evangelista, B., Ragusa, J. V., Pellegrino, K., Wu, Y., Quiroga, I. Y., Cahalan, S. E., Arooji, O. K., Madren, J. A., Schroeter, S., Cozzarin, J., et al. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4899729
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Additional file 1 of Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease
Wander, C. M., Tsujimoto, T. H. M., Ervin, J. F., Wang, C., Maranto, S. M., Bhat, V., Dallmeier, J., Wang, S. J., Lin, F.-C., Scott, W. K., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20454493
Self-citation
Additional file 5 of Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease
Wander, C. M., Tsujimoto, T. H. M., Ervin, J. F., Wang, C., Maranto, S. M., Bhat, V., Dallmeier, J., Wang, S. J., Lin, F.-C., Scott, W. K., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20454505
Self-citation
Additional file 2 of Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems
Quiroga, I. Y., Cruikshank, A. E., Bond, M. L., Reed, K. S. M., Evangelista, B., Tseng, J., Ragusa, J. V., Meeker, R. B., Won, H., Cohen, S., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19641880
Self-citation
Additional file 3 of Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice
Zamorano, M., Alexander, J. F., Catania, D., Dharmaraj, S., Kavelaars, A., & Heijnen, C. J. (2024) · Figshare · doi:10.6084/m9.figshare.26564046
Additional file 3 of Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease
Wander, C. M., Tsujimoto, T. H. M., Ervin, J. F., Wang, C., Maranto, S. M., Bhat, V., Dallmeier, J., Wang, S. J., Lin, F.-C., Scott, W. K., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20454499
Self-citation
Additional file 4 of Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease
Wander, C. M., Tsujimoto, T. H. M., Ervin, J. F., Wang, C., Maranto, S. M., Bhat, V., Dallmeier, J., Wang, S. J., Lin, F.-C., Scott, W. K., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20454502
Self-citation
Additional file 2 of Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice
Zamorano, M., Alexander, J. F., Catania, D., Dharmaraj, S., Kavelaars, A., & Heijnen, C. J. (2024) · Figshare · doi:10.6084/m9.figshare.26564043
Additional file 2 of Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease
Wander, C. M., Tsujimoto, T. H. M., Ervin, J. F., Wang, C., Maranto, S. M., Bhat, V., Dallmeier, J., Wang, S. J., Lin, F.-C., Scott, W. K., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20454496
Self-citation
Additional file 1 of Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice
Zamorano, M., Alexander, J. F., Catania, D., Dharmaraj, S., Kavelaars, A., & Heijnen, C. J. (2024) · Figshare · doi:10.6084/m9.figshare.26564040
Additional file 4 of Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice
Zamorano, M., Alexander, J. F., Catania, D., Dharmaraj, S., Kavelaars, A., & Heijnen, C. J. (2024) · Figshare · doi:10.6084/m9.figshare.26564049
Regulation of neuronal microtubule-based transport by polyglutamylation
Bodakuntla, S. (2019) · doi:10.70675/25a5f130z3b63z4663zb3aez400da5d97e80
Simvastatin rescues cognitive impairment in an Aβ1-42-induced model of Alzheimer’s disease through the HDAC2-BDNF signaling pathway
Cai, C., Chong, Y. S., Liang, H., Hu, Y., Hu, Q., Chen, J., Sajikumar, S., & Liu, F. (2026) · Neuropsychopharmacology · doi:10.1038/s41386-026-02440-z
BindingDB Entry 50011827: Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease.
BindingDB (2022) · UC San Diego · doi:10.7270/q2fx7f3b
BindingDB Entry 50014711: Synthesis and biological evaluation of selective histone deacetylase 6 inhibitors as multifunctional agents against Alzheimer's disease.
BindingDB (2022) · UC San Diego · doi:10.7270/q2hx1hhw
BindingDB Entry 50017421: Inhibition of Histone Deacetylase 6 (HDAC6) as a therapeutic strategy for Alzheimer's disease: A review (2010-2020).
BindingDB (2023) · UC San Diego · doi:10.7270/q2tb1bzk
Deciphering the effects of aging on Alzheimer’s disease based on mitochondrial dysfunction and neuroinflammation
Luo, Y., Yu, H., Zhang, J., Wu, Z., & Zhang, H. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1991837

Histone deacetylase-6 modulates Tau function in Alzheimer's disease
Qureshi, T., & Chinnathambi, S. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2022.119275 · Cited by 49 · see citing works
An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline
Trzeciakiewicz, H., Ajit, D., Tseng, J.-H., Chen, Y., Ajit, A., Tabassum, Z., Lobrovich, R., Peterson, C., Riddick, N. V., Itano, M. S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19317-4 · Cited by 102 · see citing works
Self-citation
Acetylation: a new key to unlock tau’s role in neurodegeneration
Cook, C. N., Stankowski, J. N., Carlomagno, Y., Stetler, C. T., & Petrucelli, L. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt259 · Cited by 133 · see citing works
Histone deacetylase 6 interacts with the microtubule‐associated protein tau
Ding, H., Dolan, P. J., & Johnson, G. V. W. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05564.x · Cited by 387 · see citing works
THE REGULATION OF TAU PATHOGENESIS IN NEURODEGENERATION
Trzeciakiewicz, H. (2020) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/xwcc-h138

Authors: Tseng, J.-H., Xie, L., Song, S., Xie, Y., Allen, L., Ajit, D., Hong, J.-S., Chen, X., Meeker, R. B., & Cohen, T. J.
Affiliations: University of North Carolina at Chapel Hill (US)
National Institute of Environmental Health Sciences (US)
Corresponding author: Cohen, Todd J.
ORCID: Tseng, Jui-Heng
Xie, Ling
Song, Sheng
Ajit, Deepa
Hong, Jau-Shyong
Chen, Xian
Meeker, Rick B.
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2017-08
Volume: 20
Issue: 9
Pages: 2169-2183
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2017.07.082
PMC: PMC5578720
OpenAlex: W2751317059
Cited by: 93
References: 72
Citations by year: 2026: 2 · 2025: 9 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 9 · 2020: 13 · 2019: 15 · 2018: 6
FWCI: 6.88
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 6 d)
Locations: Cell Reports (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
UNC Libraries
Funders: Alzheimer’s Association (NIRG-14-321219)
National Center for Advancing Translational Sciences (NCATS)
NIH (UL1TR001111, 1U19AI109965, R01-NS083164)
American Federation for Aging Research (AFAR) (RAG15247)
NIH/NIEHS
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: HDAC6, tau pathology, Alzheimer's disease, neuroinflammation, MMP-9, tau acetylation, tau phosphorylation, tau oligomers, aging
MeSH terms: Histone Deacetylase 6, Acetylation, Aging, Animals, Brain, Cells, Cultured, Humans, Inflammation, Phosphorylation, Mass Spectrometry, Stress, Physiological, Amyloid beta-Peptides, Neurites, tau Proteins, Mice, Knockout, Protein Multimerization

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The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

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