A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines
Open accessAbstract
Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia in the elderly. Accumulating evidence supports soluble amyloid-β (Aβ) oligomers as the leading candidate for the causative agent in AD and synapses as the primary site of Aβ oligomer action. However, the molecular and cellular mechanisms by which Aβ oligomers cause synaptic dysfunction and cognitive impairments remain poorly understood. Using primary cultures of rat hippocampal neurons as a model system, we show that the partitioning defective-1 (PAR-1)/microtubule affinity-regulating kinase (MARK) family kinases act as critical mediators of Aβ toxicity on synapses and dendritic spines. Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. Our results reveal a critical role for PAR-1/MARK kinases in AD pathogenesis and suggest PAR-1/MARK inhibitors as potential therapeutics for AD and possibly other tauopathies where aberrant tau hyperphosphorylation is involved.
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Studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity depends on tau phosphorylation at these sites.
“Notably, studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity caused by Aβ depends on tau phosphorylation at these sites [39, 45, 56–58].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [45]
In 'Expression of non-phosphorylatable form of tau blocks Aβ toxicity' (page not available), Aβ increased tau phosphorylation at the 12E8 sites in cultured rat hippocampal neurons, and non-phosphorylatable tau ameliorated Aβ-induced spine and synaptic-marker loss. The Introduction and 'Expression of a non-phosphorylatable form of tau blocks PAR-1/MARK toxicity' describe Drosophila evidence that PAR-1-site phosphorylation is required for tau toxicity, but do not show Aβ-induced augmentation of tau toxicity in transgenic Drosophila. (LLM, conf=0.86)
Experimental — accuracy not yet measuredActivities of GSK3 and PAR-1/MARKs are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity.
“the activities of two major tau kinases, GSK3 and PAR-1/microtubule affinity-regulating kinases (MARKs), are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity [37, 39, 43–45].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [45]
The Introduction and the section ‘Expression of non-phosphorylatable form of tau blocks Aβ toxicity’ link PAR-1/MARK-mediated tau phosphorylation to tau toxicity and Aβ-induced synaptic and spine damage (page numbers unavailable). Our copy does not establish the corresponding role for GSK3 or state that either kinase causes tau to detach from microtubules. (LLM, conf=0.87)
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Cites
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · see citing works
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480 · see citing works
Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J., & Sabatini, B. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4970-06.2007 · Cited by 1,592 · see citing works
LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600110 · Cited by 1,381 · see citing works
Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.040 · Cited by 1,294 · see citing works
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · cited 7× · see citing works
“It also remains to be determined whether Ab oligomers act by directly activating transmembrane receptors, changing neuronal membrane properties or, simply, causing cellular stress (4,34).”
BackgroundResultInfluentialSpires, T. L., Meyer-Luehmann, M., Stern, E. A., McLean, P. J., Skoch, J., Nguyen, P. T., Bacskai, B. J., & Hyman, B. T. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1879-05.2005 · Cited by 550 · cited 1× · see citing works
“Accumulating evidence support that A is the primary agent causative of synaptic and spine pathology in AD [3,4,5].”
BackgroundBeta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses
Almeida, C. G., Tampellini, D., Takahashi, R. H., Greengard, P., Lin, M. T., Snyder, E. M., & Gouras, G. K. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.02.008 · Cited by 397 · see citing works
Knowles, J. K., Rajadas, J., Nguyen, T.-V. V., Yang, T., LeMieux, M. C., Vander Griend, L., Ishikawa, C., Massa, S. M., Wyss-Coray, T., & Longo, F. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0620-09.2009 · Cited by 184 · see citing works
Self-citationWang, J.-W., Imai, Y., & Lu, B. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5094-06.2007 · Cited by 80 · cited 3× · see citing works
“Several kinases have been shown to act upstream of PAR-1/MARK (42), including LKB1 (33).”
BackgroundResultSelf-citation
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Research works printed but not linked: 3
- Jin, M., Shepardson, N., Yang, T., Chen, G., Walsh, D. and Selkoe, D.J. (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl Acad. Sci. USA, 108, 5819-5824.
- Rapoport, M., Dawson, H.N., Binder, L.I., Vitek, M.P. and Ferreira, A. (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA, 99, 6364-6369.
- Gylys, K.H., Fein, J.A., Yang, F., Wiley, D.J., Miller, C.A. and Cole, G.M. (2004) Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am. J. Pathol., 165, 1809-1817.
Cited by
Sorted by citations
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758 · see citing works
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Ambadipudi, S., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M. (2017) · Nature Communications · doi:10.1038/s41467-017-00480-0 · Cited by 782 · see citing works
Tau Aggregation and Its Interplay with Amyloid-β
Nisbet, R. M., Polanco, J.-C., Ittner, L. M., & Götz, J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-014-1371-2 · Cited by 359 · see citing works
Mairet-Coello, G., Courchet, J., Pieraut, S., Courchet, V., Maximov, A., & Polleux, F. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.003 · Cited by 351 · see citing works
Soluble forms of tau are toxic in Alzheimer's disease
Kopeikina, K., Hyman, B., & Spires-Jones, T. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0032-y · Cited by 232 · see citing works
An acetylation–phosphorylation switch that regulates tau aggregation propensity and function
Carlomagno, Y., Chung, D.-E. C., Yue, M., Castanedes-Casey, M., Madden, B. J., Dunmore, J., Tong, J., DeTure, M., Dickson, D. W., Petrucelli, L., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.794602 · Cited by 143 · see citing works
The dendritic hypothesis for Alzheimer's disease pathophysiology
Cochran, J. N., Hall, A. M., & Roberson, E. D. (2014) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.12.004 · Cited by 114 · see citing works
Rovelet-Lecrux, A., Charbonnier, C., Wallon, D., Nicolas, G., Seaman, M. N. J., Pottier, C., Breusegem, S. Y., Mathur, P. P., Jenardhanan, P., Le Guennec, K., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.100 · Cited by 106 · see citing works
Ando, K., Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., & Iijima, K. M. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1005917 · Cited by 105 · see citing works
Hannan, S. B., Dräger, N. M., Rasse, T. M., Voigt, A., & Jahn, T. R. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13532 · Cited by 38 · see citing works
- Authors
- Yu, W., Polepalli, J., Wagh, D., Rajadas, J., Malenka, R., & Lu, B.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Lu, Bingwei
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-12-08
- Volume
- 21
- Issue
- 6
- Pages
- 1384-1390
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3284124
- OpenAlex
- W2114205908
- Cited by
- 103
- References
- 11
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 6 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 10 · 2016: 8 · 2015: 7 · 2014: 15 · 2013: 9 · 2012: 6
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McKnight Foundation
- School of Medicine, Stanford University
- National Institute of Mental Health (R01MH063394, R01MH080378)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054926)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta oligomers, MARK4, tau hyperphosphorylation, dendritic spines, synapses, synaptic dysfunction, hippocampal neurons, tauopathy, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Electrophysiology, Fluorescent Antibody Technique, Hippocampus, Microtubules, Mutation, Neurons, Phosphorylation, Synapses, Amyloid beta-Peptides, tau Proteins, Protein Serine-Threonine Kinases, Dendritic Spines, Rats
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