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Aβ Oligomers Cause Localized Ca 2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines
Open accessAbstract
Aggregation of amyloid-β (Aβ) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Aβ-cascade hypothesis, Aβ is considered toxic for neurons and Tau a downstream target of Aβ. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Aβ oligomers. Initial events become evident by missorting of endogenous Tau into the somatodendritic compartment, in contrast to axonal sorting in normal neurons. In missorted dendritic regions there is a depletion of spines and local increase in Ca 2+ , and breakdown of microtubules. Tau in these regions shows elevated phosphorylation at certain sites diagnostic of AD-Tau (e.g., epitope of antibody 12E8, whose phosphorylation causes detachment of Tau from microtubules, and AT8 epitope), and local elevation of certain kinase activities (e.g., MARK/par-1, BRSK/SADK, p70S6K, cdk5, but not GSK3β, JNK, MAPK). These local effects occur without global changes in Tau, tubulin, or kinase levels. Somatodendritic missorting occurs not only with Tau, but also with other axonal proteins such as neurofilaments, and correlates with pronounced depletion of microtubules and mitochondria. The Aβ-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Aβ-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. By contrast, the rise in Ca 2+ levels, kinase activities, and Tau phosphorylation cannot be prevented by taxol. Incipient and local changes similar to those of Aβ oligomers can be evoked by cell stressors (e.g., H 2 O 2 , glutamate, serum deprivation), suggesting some common mechanism of signaling.
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“mis-localization to dendrites and spines causing neurotoxicity [52]”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [52]
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“Under normal conditions, tau is primarily localized to axons and promotes formation and stabilization of microtubules; however, in AD, tau becomes hyperphosphorylated and mislocalizes to somatodendritic compartments (Avila et al., 2004, Ittner et al., 2010, Zempel et al., 2010).”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Zempel et al., 2010
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“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 [39]
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“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 [39]
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“Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD [2, 35–41].”
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 [39]
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“In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”
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 [39]
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“Ab oligomers also cause tau mislocalization (77,78).”
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“Under normal conditions, tau is primarily localized to axons and promotes formation and stabilization of microtubules; however, in AD, tau becomes hyperphosphorylated and mislocalizes to somatodendritic compartments (Avila et al., 2004, Ittner et al., 2010, Zempel et al., 2010).”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Zempel et al., 2010
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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · cited 1×
“We also note that in our preparations we did not consistently observe a band at 56 kDa, a species that has been reported to be toxic for transgenic mice (Lesné et al., 2006) but can be visualized in certain conditions (Walsh et al., 2005; Ashe, 2006; Bernstein et al., 2009).”
BackgroundRetractedSoluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · cited 1×
“Despite numerous studies on the pathway of APP misprocessing and its consequences for neurons the modes of A toxicity have remained enigmatic (Haass and Selkoe, 2007; Small and Duff, 2008).”
BackgroundCommon structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064 · cited 1×
“Nevertheless, there were differences in structure because dot blots with antibody A11, which recognizes a more toxic generic amyloid conformation (Kayed et al., 2003), were more intense for F12 medium than for Nb (Fig.”
BackgroundDiffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
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 · cited 3×
“There is a moderate decrease of ATP which is more apparent with F12 than with Nb medium, suggesting that F12, which was used in the original procedure (Lambert et al., 1998), could have some toxic effects on its own.”
BackgroundMethodTau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174 · cited 1×
“These include loss of synapses and neurons, deficiency in neurotransmitters and metabolism, aggregation of amyloid- (A )-peptides into extracellular “amyloid plaques” and Tau protein into intracellular “neurofibrillary tangles” (Selkoe, 2004; Binder et al., 2005; Ballatore et al., 2007).”
BackgroundReducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892 · cited 1×
“…conversely Tau is considered necessary for the progression of neurodegeneration, as seen in cell and animal models (Rapoport et al., 2002; King et al., 2006; Roberson et al., 2007), and indeed the Tau pathology correlates well with clinical symptoms (Braak and Braak, 1991; Clavaguera et al., 2009).”
BackgroundTransmission and spreading of tauopathy in transgenic mouse brain
Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1901 · Cited by 1,803
Physiology and Pathophysiology of Purinergic Neurotransmission
Burnstock, G. (2007) · Physiological Reviews · doi:10.1152/physrev.00043.2006 · Cited by 1,609 · cited 1×
“We also tested extracellular ATP (100 M, 3 h), which functions as a stress signal and induces Ca 2 influx via P2 receptors and has been implicated in neurodegenerative disease (Burnstock, 2007).”
MethodShankar, 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 · cited 1×
“4e,f), and involving NMDA receptors and others (De Felice et al., 2007; Shankar et al., 2007).”
BackgroundThe axonal transport of mitochondria
Saxton, W. M., & Hollenbeck, P. J. (2012) · Journal of Cell Science · doi:10.1242/jcs.053850 · Cited by 1,218 · cited 1×
“As shown previously (Stamer et al., 2002; Hollenbeck and Saxton, 2005; Thies and Mandelkow, 2007), such mitochondrial traffic jams cause a local drop of energy (ATP) and consequently spine destruction through the perturbation of the actin network and loss of synaptic components (Whiteman et al.,…”
Background
Research works printed but not linked: 3
- 10.1242/jcs.02745 · DOI · Paper page
- 10.1074/jbc.R800036200 · DOI
- 10.1186/1750-1326-4-48 · DOI · Paper page
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Items 301–400 of 593
Abnormal kalirin signaling in neuropsychiatric disorders
Remmers, C. L., Sweet, R. A., & Penzes, P. (2013) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.12.006 · Cited by 45
“However, tau’s dendritic mechanisms are just merging (Zempel et al., 2010), leaving unclear how it may interact ith other mediators of dendritic spine loss engaged by soluble A . imilarly, whether tau interacts directly with kalirin is unknown, lthough kalirin-9 and kalirin-12 contain RhoA GEF…”
BackgroundCorsetti, V., Borreca, A., Latina, V., Giacovazzo, G., Pignataro, A., Krashia, P., Natale, F., Cocco, S., Rinaudo, M., Malerba, F., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa039 · Cited by 42
Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice
Velázquez, R., Meechoovet, B., Ow, A., Foley, C., Shaw, A. Y., Smith, B. E., Oddo, S., Hulme, C., & Dunckley, T. L. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01684-9 · Cited by 44
Oka, M., Fujisaki, N., Akiko, M.-O., Ohtake, Y., Shimizu, S., Saito, T., Hisanaga, S., Iijima, K., & Ando, K. (2017) · The Journal of Biochemistry · doi:10.1093/jb/mvx038 · Cited by 41
Ye, X., Feng, T., Tammineni, P., Chang, Q., Jeong, Y. Y., Margolis, D. J., Cai, H., Kusnecov, A. W., & Cai, Q. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2851-16.2017 · Cited by 62
“Mutant hAPP Tg mouse brains displayed a significant increase in synaptosomal BACE1 (15.28 4.25; p 0.05), Rab7, an LE marker (1.43 0.17; p 0.05), APP (2.18 0.02; p 0.001), and with C99 and A , relative to those of their WT littermates.”
BackgroundInfluentialAPOE ε4 carriers may undergo synaptic damage conferring risk of Alzheimer's disease
Sun, X., Dong, C., Levin, B. E., Crocco, E., Loewenstein, D., Zetterberg, H., Blennow, K., Wright, C. B., & Initiative, A. D. N. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.05.003 · Cited by 44
Mota, S. I., Ferreira, I. L., Pereira, C., Oliveira, C. R., & Rego, A. C. (2012) · Current Alzheimer Research · doi:10.2174/156720512802455322 · Cited by 42
“Also in primary hippocampal neurons, Zempel and colleagues [13] demonstrated that A oligomers induce spine loss, tau missorting and microtubule depletion.”
BackgroundInfluentialZhang, Z.-H., Chen, C., Wu, Q., Zheng, R., Liu, Q., Ni, J., Hoffmann, P. R., & Song, G.-L. (2016) · Metallomics · doi:10.1039/c6mt00117c · Cited by 38
It cuts two ways: microtubule loss during Alzheimer disease
Jean, D. C., & Baas, P. W. (2013) · EMBO Journal · doi:10.1038/emboj.2013.219 · Cited by 36
“In AD, tau invades dendrites abnormally through deregulation of its normal sorting mechanism, and this somehow leads to microtubule loss from dendrites (Zempel et al , 2010).”
Axonal Transport and Mitochondrial Dysfunction in Alzheimer's Disease
Riemer, J., & Kins, S. (2012) · Neurodegenerative Diseases · doi:10.1159/000342020 · Cited by 39
Kirkwood, C. M., Ciuchta, J., Ikonomovic, M. D., Fish, K. N., Abrahamson, E. E., Murray, P. S., Klunk, W. E., & Sweet, R. A. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31829ecc89 · Cited by 35
“Western blot analyses provide clear evidence that 6E10 and 4G8 are reactive with soluble monomeric and oligomeric species of AA (26, 27).”
BackgroundInfluentialWhen, where and how? Focus on neuronal calcium dysfunctions in Alzheimer’s Disease
Agostini, M., & Fasolato, C. (2016) · Cell Calcium · doi:10.1016/j.ceca.2016.06.008 · Cited by 40
Smith, D. K., He, M., Zhang, C., & Zheng, J. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.01.006 · Cited by 34
“Ab oligomers promote this mislocalization via members of the microtubule affinity-regulating kinase family (Zempel et al., 2010) and reductions in MAPT concentration inhibit both Ab-dependent and APOE4-dependent neuronal deficits in vitro and in vivo, respectively (Andrews-Zwilling et al., 2010;…”
BackgroundOchiishi, T., Kaku, M., Kiyosue, K., Doi, M., Urabe, T., Hattori, N., Shimura, H., & Ebihara, T. (2019) · Scientific Reports · doi:10.1038/s41598-019-53415-8 · Cited by 34
Bandaru, L. J. M., Ayyalasomayajula, N., Murumulla, L., & Challa, S. (2022) · BioMetals · doi:10.1007/s10534-021-00360-7 · Cited by 39
“Changes in these kinases in tau phosphorylation and the loss of a microtubule network further impair mitochondrial trafficking (Zempel et al. 2010).”
BackgroundDendritic/Post-synaptic Tau and Early Pathology of Alzheimer’s Disease
Yin, X., Zhao, C., Qiu, Y., Zhou, Z., Bao, J., & Qian, W. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.671779 · Cited by 41
“Exposure to oligomeric Aβ increases levels of tau in dendrites in AD (Zempel et al., 2010).”
BackgroundRemodeling of Intracellular Ca2+ Homeostasis in Rat Hippocampal Neurons Aged In Vitro
Calvo-Rodriguez, M., Hernando-Pérez, E., López-Vázquez, S., Núñez, J., Villalobos, C., & Núñez, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041549 · Cited by 34
“However, it has been claimed that some of these results are related to glutamate contamination of the media in which the synthetic Aβo were prepared [26,27].”
ResultRole of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution
Vergara, C., Ordóñez‐Gutiérrez, L., Wandosell, F. G., Ferrer, I., del Rı́o, J. A., & Gavı́n, R. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8793-7 · Cited by 38
Amyloid beta1-42 peptide regulates microtubule stability independently of tau
Pianu, B., Lefort, R., Thuiliere, L., Tabourier, E., & Bartolini, F. (2014) · Journal of Cell Science · doi:10.1242/jcs.143750 · Cited by 30
“…exposures to Ab can induce MT stability in neurons challenges the current interpretation that a primary activity of Ab is to cause MT destabilization through tau hyperphosphorylation (Michaelis et al., 1998) (Ballatore et al., 2012; Michaelis et al., 2005; Zempel et al., 2010; Zhang et al., 2012).”
BackgroundHärtig, W., Saul, A., Kacza, J., Grosche, J., Goldhammer, S., Michalski, D., & Wirths, O. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12050 · Cited by 30
Zhang, X., Chen, C., & Liu, Y. (2024) · Alzheimer's Research & Therapy · doi:10.1186/s13195-024-01430-x · Cited by 34
“Second, Aβ modifies the post-translational modifications (PTMs) or distribution of tau, thereby converting tau into an active agent in the development of Aβ-induced neuronal dysfunction [14] (Fig.”
BackgroundYang, T., Tran, K. C., Zeng, A. Y., Massa, S. M., & Longo, F. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-77210-y · Cited by 40
Balaji, V., Kaniyappan, S., Mandelkow�, E., Wang, Y., & Mandelkow, E.-M. (2018) · Autophagy · doi:10.1080/15548627.2018.1509607 · Cited by 33
“(d) Quantification of the spine density of the dendrites on the neuritic side after treatment with DMSO or with protein degradation inhibitors (n = 17–20 dendrites from 3 experiments; one-way ANOVA with Tukey’s post hoc test; F [2,6] = 39.”
BackgroundMethodResultInfluentialSelf-citationDifferences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer’s Disease
Gelman, S., Palma, J. D., Tombaugh, G. C., & Ghavami, A. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170457 · Cited by 36
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Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy
Rossi, D., Gruart, A., Contreras-Murillo, G., Muhaisen, A., Ávila, J., Delgado-García, J. M., Pujadas, L., & Soriano, E. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101743 · Cited by 30
Takach, O. P., Gill, T. B., & Silverman, M. A. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.11.018 · Cited by 34
“In contrast, other forms of AbO toxicity such as cytoskeletal wreckage, Golgi fragmentation, and synaptic dysfunction are seemingly irreversible and lead to cell death (Joshi et al., 2014;Miller et al., 2014; Zempel et al., 2010).”
Takamura, A., Sato, Y., Watabe, D., Okamoto, Y., Nakata, T., Kawarabayashi, T., Oddo, S., LaFerla, F. M., Shoji, M., & Matsubara, E. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.04.038 · Cited by 33
Editorial: Mitochondrial Dysfunction and Neurodegeneration
Tapias, V. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01372 · Cited by 35
“Elevated Ca2+ influx plays a key role in promoting pathological tau phosphorylation via modulation of Ca2+-binding proteins and/or dysregulation of the enzymatic activity of kinases and phosphatases (Zempel et al., 2010; MairetCoello et al., 2013).”
BackgroundMelatonin interacts with repeat domain of Tau to mediate disaggregation of paired helical filaments.
Balmik, A., Das, R., Dangi, A., Gorantla, N. V., Marelli, U., & Chinnathambi, S. (2019) · Biochimica et Biophysica Acta - General Subjects · doi:10.1016/j.bbagen.2019.129467 · Cited by 31
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“Moreover, hippocampal primary neurons exposed to Aβ oligomers show an evident missorting of endogenous tau into the somatodendritic compartment (Zempel et al., 2010).”
BackgroundHypothalamic-Pituitary-Thyroid Axis in Patients with Alzheimer Disease (AD)
Yong-Hong, L., Peng, X., Changquan, H., Yang, B., & Qing‐Xiu, L. (2013) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e318280aafb · Cited by 33
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“Accumulation of aggregated Ab in the AD brain has been reported to disrupt calcium metabolism with concomitant downstream cytotoxic effects such as mitochondrial dysfunction, activation of caspases [64,65] microtubule destabilisation and tau phosphorylation [66].”
BackgroundKrause, G. J., Kirchner, P., Stiller, B., Morozova, K. S., Díaz, A., Chen, K., Krogan, N. J., Agulló-Pascual, E., Clement, C. C., Lindenau, K. L., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113529 · Cited by 30
The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders
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“These data are supported by the finding that Aβ causes missorting of endogenous tau into the dendritic compartment (Zempel et al., 2010).”
BackgroundResultMechanisms of Axonal Sorting of Tau and Influence of the Axon Initial Segment on Tau Cell Polarity
Zempel, H., & Mandelkow�, E. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_6 · Cited by 30
Self-citationAlzheimer's disease and synapse Loss: What can we learn from induced pluripotent stem Cells?
Rodríguez-Jiménez, F. J., Ureña‐Peralta, J. R., Jendelová, P., & Erceg, S. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2023.01.006 · Cited by 33
Kinase Signaling in Dendritic Development and Disease
Nourbakhsh, K., & Yadav, S. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.624648 · Cited by 31
“Defects in axonal trafficking of tau promotes axonal degeneration and corresponding decrease in synaptic inputs (Zempel et al., 2010).”
BackgroundForest, K. H., Alfulaij, N., Arora, K., Taketa, R., Sherrin, T., Todorovic, C., Lawrence, J. L. M., Yoshikawa, G. T., Ng, H. L., Hruby, V. J., et al. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14257 · Cited by 28
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Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms
Ott, S., Dziadulewicz, N., & Crowther, D. C. (2015) · Disease Models & Mechanisms · doi:10.1242/dmm.019042 · Cited by 23
“product of disease-linked mitochondrial dysfunction (Hirai et al., 2001; la Monte and Wands, 2006; Onyango et al., 2006; Zempel et al., 2010) or thirdly as a result of an inflammatory response to amyloid deposition (Perry et al.”
Whiteman, I. T., Minamide, L. S., Goh, D. L., Bamburg, J. R., & Goldsbury, C. S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020878 · Cited by 29
Secker, C., Motzny, A., Kostova, S., Buntru, A., Helmecke, L., Reus, L., Steinfort, R., Brusendorf, L., Boeddrich, A., Neuendorf, N., et al. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15842 · Cited by 28
“…the accumulation of extracellular deposits (Gyure et al., 2001; Wirths et al., 2001) and that these structures can promote tau aggregation (Götz et al., 2001; He et al., 2018; Zempel et al., 2010), which is associated with neuronal dysfunction and progression of disease (Zhou et al., 2017).”
Scala, C. D., Armstrong, N., Chahinian, H., Chabrière, É., Fantini, J., & Yahi, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113383 · Cited by 31
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“Increases in intracel lular synapt ic ca lc ium concentration are associated with neuronal dysfunction and have been implicated in the pathogenesis of AD (22).”
BackgroundAMPK Ameliorates Tau Acetylation and Memory Impairment Through Sirt1
Wang, L., Shi, F.-X., Li, N., Cao, Y., Lei, Y., Wang, J., Tian, Q., & Zhou, X. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02079-x · Cited by 34
Brain regional synchronous activity predicts tauopathy in 3×TgAD mice
Liu, D., Lu, H., Stein, E. A., Zhou, Z., Yang, Y., & Mattson, M. P. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.06.016 · Cited by 28
“Overactivation of glutamate receptors can induce pathogenic tau accumulation in hippocampal neurons in culture and in vivo by a mechanism involving excessive Ca2+ influx (Elliott et al., 1993; Mattson, 1990; Mairet-Coello et al., 2013; Zempel et al., 2010).”
BackgroundEpelbaum, S., Youssef, I., Lacor, P. N., Chaurand, P., Duplus, E., Brugg, B., Duyckaerts, C. J., & Delatour, B. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.03.005 · Cited by 30
Saydoff, J. A., Olariu, A., Sheng, J. G., Hu, Z., Li, Q., Garcia, R. A. G., Pei, J., Sun, G. Y., & von Borstel, R. W. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130059 · Cited by 36
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Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression
Grundman, J., Spencer, B., Sarsoza, F., & Rissman, R. A. (2021) · PLOS ONE · doi:10.1371/journal.pone.0251611 · Cited by 27
“Moreover, there is evidence that Aβ may influence the localization of tau within neurons [38].”
BackgroundDendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice
Walker, C. K., Greathouse, K. M., Boros, B. D., Poovey, E. H., Clearman, K. R., Ramdas, R., Muhammad, H. M., & Herskowitz, J. H. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2020.12.006 · Cited by 27
“Under normal conditions, tau is primarily localized to axons and promotes formation and stabilization of microtubules; however, in AD, tau becomes hyperphosphorylated and mislocalizes to somatodendritic compartments (Avila et al., 2004, Ittner et al., 2010, Zempel et al., 2010).”
BackgroundThe key roles of organelles and ferroptosis in Alzheimerʼs disease
Long, H., Cheng, Y., Zhou, Z., Luo, H., Wen, D., & Gao, L. (2022) · Journal of Neuroscience Research · doi:10.1002/jnr.25033 · Cited by 28
“At the molecular level, the accumulation of Aβ causes Ca2+ influx (Zempel et al., 2010), which activates calprotease, thereby increasing the cleavage of P25– P35, where P25 activates CDK5 and finally phosphorylates GRASP65.”
BackgroundElucidating the Triggers, Progression, and Effects of Alzheimer's Disease
Medeiros, R., Chabrier, M. A., & LaFerla, F. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-129009 · Cited by 26
Infection‐induced endothelial amyloids impair memory
Balczon, R., Pittet, J., Wagener, B. M., Moser, S. A., Voth, S. B., Vorhees, C. V., Williams, M. T., Bridges, J. P., Alvarez, D. F., Koloteva, A., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201900322r · Cited by 28
Rankovic, M., & Zweckstetter, M. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.12.014 · Cited by 25
Role of cellular prion protein in interneuronal amyloid transmission
del Rı́o, J. A., Ferrer, I., & Gavı́n, R. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.03.001 · Cited by 30
Mokhtar, S. H., Kim, M., Magee, K. A., Aui, P., Thomas, S., Bakhuraysah, M. M., Alrehaili, A. A., Lee, J. Y., Steer, D., Kenny, R., et al. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.233451 · Cited by 25
“Oligomeric Aβ has been shown to disrupt the microtubule cytoskeleton and cause neuritic dystrophy from the postsynaptic density (Zempel et al., 2010; Jin et al., 2011).”
Arora, K., Alfulaij, N., Higa, J. K., Panee, J., & Nichols, R. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.453746 · Cited by 29
“A -induced mitochondrial mislocalization was also confirmed in hippocampal neurons (36).”
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Therapeutic Strategies Targeting Amyloid-β Receptors and Transporters in Alzheimer’s Disease
Lao, K., Zhang, R., Luan, J., Zhang, Y., & Gou, X. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-200851 · Cited by 25
“…[5], the imbalance between A (cid:2) production and clearance leads to gradual accumulation and aggregation of the peptide in the brain, thereby initiating a neurodegenerative cascade that involves tau pathology [6, 7], inflammation [8], oxidative stress [9], and neuronal injury and loss [10, 11].”
Diagnostic and prognostic biomarkers for HAND
McLaurin, K. A., Booze, R. M., & Mactutus, C. F. (2019) · Journal of NeuroVirology · doi:10.1007/s13365-018-0705-6 · Cited by 25
“Tau is a microtubule-associated binding protein located preferentially in axons (Binder et al. 1985) and, albeit in small amounts, in dendrites and dendritic spines (e.g., Zempel et al. 2010; Kopeikina et al. 2013).”
BackgroundCroft, C. L., Kurbatskaya, K., Hanger, D. P., & Noble, W. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-07906-1 · Cited by 23
Luo, J., Wärmländer, S., Gräslund, A., & Abrahams, J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.a116.714576 · Cited by 24
“Extracellular fibrillar and oligomeric A peptides seem to promote tau hyperphosphorylation, thereby inducing loss of tau’s microtubule binding activity, leading to neural dysfunction and degeneration (30).”
BackgroundThe Cellular Distribution and Ser262 Phosphorylation of Tau Protein Are Regulated by BDNF In Vitro
Chen, Q., Zhou, Z., Zhang, L., Xu, S., Chen, C., & Yu, Z. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091793 · Cited by 26
“peroxide treatment, or Ab oligomer treatment [32].”
BackgroundWang, X., Kastanenka, K. V., Arbel‐Ornath, M., Commins, C., Kuzuya, A., Lariviere, A., Krafft, G. A., Hefti, F. F., Jerecìć, J., & Bacskai, B. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-22979-2 · Cited by 32
Cochran, J. N., Diggs, P., Nebane, N. M., Rasmussen, L. A., White, E. L., Bostwick, R. J., Maddry, J. A., Suto, M. J., & Roberson, E. D. (2014) · SLAS DISCOVERY · doi:10.1177/1087057114547232 · Cited by 25
Modelling Tauopathies in Drosophila : Insights from the Fruit Fly
Cowan, C. M., Sealey, M. A., Quraishe, S., Targett, M.-T., Marcellus, K. A., Allan, D. W., & Mudher, A. K. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/598157 · Cited by 26
Buchholz, S., Kabbani, M. A. A., Bell‐Simons, M., Kluge, L., Cagmak, C., Klimek, J., Haag, N., Iohan, L. D. C. C., Coulon, A., Costa, M. R., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14403 · Cited by 21
“9,45,71 Pathological mis-sorting of tau and reduced neuronal activity measured by calcium oscillations were observed shortly after A β O exposure in our neurons, which was abolished after sustained exposure.”
Self-citationJarero-Basulto, J. J., Rivera-Cervantes, M. C., Gasca‐Martínez, D., García‐Sierra, F., Gasca-Martínez, Y., & Beas‐Zárate, C. (2020) · Pharmaceuticals · doi:10.3390/ph13120424 · Cited by 27
Enhanced Tau Protein Translation by Hyper-Excitation
Kobayashi, S., Tanaka, T., Soeda, Y., & Takashima, A. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00322 · Cited by 22
“Since the shift in localization of tau from a predominantly axonal site to somatodendritic site occurs during early stages of neurodegeneration (Zempel et al., 2010; Zempel and Mandelkow, 2014), the consensus now holds that tau aggregates start to form from accumulations of phosphorylated tau in…”
BackgroundJang, J. K., Park, K. J., Lee, J. H., Ko, K. Y., Kang, S., & Kim, I. Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.03.060 · Cited by 23
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Nakanishi, N., Ryan, S. D., Zhang, X., Khan, A. U., Holland, T., Cho, E.-G., Huang, X., Liao, F., Xu, H., Lipton, S. A., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4646-10.2013 · Cited by 18
“cytoskeleton, aggregate formation of phosphorylated tau, and neuronal death (De Felice et al., 2008; Zempel et al., 2010; Jin et al., 2011).”
BackgroundMethodInfluentialSensing change: the emerging role of calcium sensors in neuronal disease.
Seaton, G., Hogg, E. L., Jo, J., Whitcomb, D. J., & Cho, K. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.07.014 · Cited by 22
Teravskis, P. J., Ashe, K. H., & Liao, D. (2020) · The Neuroscientist · doi:10.1177/1073858420916696 · Cited by 31
Christensen, K. R., Beach, T. G., Serrano, G. E., & Kanaan, N. M. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0675-9 · Cited by 23
“In addition, rat primary hippocampal neuron cultures exposed to Aβ oligomers showed an increased redistribution of tau to the somatodendritic compartment, and subsequent analyses found an increase in phosphorylation, including at the AT8 epitope, of this somatodendritic tau compared to untreated cultures [78], indicat…”
BackgroundRosetta Stone for Amyloid Fibrils: The Key Role of Ring-Like Oligomers in Amyloidogenesis
Galzitskaya, O. V., & Selivanova, O. M. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170230 · Cited by 28
Vagnoni, A., Glennon, E. B. C., Perkinton, M. S., Gray, E. H., Noble, W. J., & Miller, C. C. J. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt313 · Cited by 20
Epigenetic modifications of DNA and RNA in Alzheimer’s disease
Martínez-Feduchi, P., Jin, P., & Yao, B. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1398026 · Cited by 22
Caballero, E., Hernando-Pérez, E., Tapias, V., Calvo-Rodríguez, M., Villalobos, C., & Núñez, L. (2022) · Biomedicines · doi:10.3390/biomedicines10051153 · Cited by 23
“However, the medium utilized for oligomerization can contain traces of glutamate receptor agonists [43], thus questioning this hypothesis.”
BackgroundYe, T., Li, X., Zhou, P., Ye, S., Gao, H., Hua, R., Ma, J., Wang, Y., & Cai, B. (2020) · 3 Biotech · doi:10.1007/s13205-020-2103-z · Cited by 18
“The calcium homeostasis imbalance in neurons is an important factor in the progress of AD, and the increase of intracellular calcium concentration could stimulate the phosphorylation of tau (MAPT; commonly known as tau) (Müller et al. 2011; Zempel et al. 2010).”
BackgroundDynamic effect of beta-amyloid 42 on cell mechanics
Gao, Q., Fang, Y., Zhang, S., Wong, H. S. H., Chan, Y. E., Wong, S. S. M., Yung, K. K. L., & Lai, K. W. C. (2019) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2019.01.046 · Cited by 21
Arora, K., Cheng, J., & Nichols, R. A. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.634162 · Cited by 21
“Regulation of PHF-tau and pFyn following Sustained Exposure of Neuronal Cultures Expressing 4 2-nAChRs to A —Mislocalization of hyperphosphorylated tau (and, consequently, PHF-tau) has been widely proposed to be a downstream effector of A toxicity (28, 29).”
BackgroundCerebrospinal fluid biomarkers for pathological processes in Alzheimer's disease
Rosén, C., & Zetterberg, H. (2013) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e32835f6747 · Cited by 23
Membrane interaction to intercellular spread of pathology in Alzheimer’s disease
Valappil, D. K., Mini, N. J., Dilna, A., & Nath, S. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.936897 · Cited by 19
“Oligomerization may happen in several stages, the transformation of non-toxic monomers to oligomers and protofibrils can trigger neuronal damage (Hashimoto et al., 2003; Zempel et al., 2010).”
BackgroundFantini, J., Azzaz, F., Scala, C. D., Aulas, A., Chahinian, H., & Yahi, N. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108797 · Cited by 20
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“In agreement with earlier reports (Hoover et al., 2010; Zempel et al., 2010), we observed that Aβ leads to an accumulation of hyperphosphorylated Tau in dendritic spines; the latter event is believed to activate a pathway that upregulates GluN2B receptor expression which, in turn, culminates in…”
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“Finally, A 42-induced microtubule depletion and loss of spines [44] as well as a retraction of synaptic contacts [45] were also observed.”
BackgroundNichols, T. W. (2014) · Journal of Alzheimer’s Disease & Parkinsonism · doi:10.4172/2161-0460.1000159 · Cited by 17
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Virus-Induced Membrane Fusion in Neurodegenerative Disorders
Osorio, C. P., Sfera, A., Anton, J. J., Thomas, K. G., Andronescu, C. V., Li, E., Yahia, R., Avalos, A. G., & Kozlakidis, Z. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.845580 · Cited by 23
“Indeed, clinical and preclinical studies have shown that increased intracellular Ca2+ can lead to Tau hyperphosphorylation (Etcheberrigaray et al., 1998; Zempel et al., 2010; Cao et al., 2019).”
BackgroundTjiang, N., & Zempel, H. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04150-3 · Cited by 21
Self-citation
Metadata
- Authors
- Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Mandelkow, Eva-Maria
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-09-08
- Volume
- 30
- Issue
- 36
- Pages
- 11938-11950
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6633549
- OpenAlex
- W2041956586
- Cited by
- 686
- References
- 70
- Citations by year
- 2026: 29 · 2025: 33 · 2024: 27 · 2023: 22 · 2022: 30 · 2021: 38 · 2020: 54 · 2019: 46 · 2018: 49 · 2017: 46 · 2016: 50 · 2015: 51 · 2014: 61 · 2013: 54 · 2012: 50
- FWCI
- 32.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- amyloid-beta oligomers, Alzheimer's disease, tau phosphorylation, dendrites, microtubule destabilization, dendritic spines, neurofilaments, mitochondria, paclitaxel, p70S6K, cyclin-dependent kinase 5, hippocampal neurons, axonal transport, oxidative stress, glutamate, serum deprivation
- MeSH terms
- Adenosine Triphosphate, Analysis of Variance, Animals, Calcium, Cells, Cultured, Dendrites, Embryo, Mammalian, Hippocampus, L-Lactate Dehydrogenase, Microtubules, Mitochondria, Neurons, Peptide Fragments, Phosphorylation, Protein Kinases, Time Factors, Amyloid beta-Peptides, tau Proteins, Neurofilament Proteins, Rats, Sprague-Dawley, Protein Transport, Microscopy, Electron, Transmission, Dendritic Spines, Rats
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