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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
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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
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“…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).”
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Physiology and Pathophysiology of Purinergic Neurotransmission
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“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.,…”
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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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The Extracellular Protein, Transthyretin Is an Oxidative Stress Biomarker
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“It is also believed that protein oligomers elevate the production of ROS which causes the oxidative stress and vice versa causing cell damage (Zempel et al., 2010).”
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“A subsequent study found that Aβ causes a range of deleterious effects on TAU including its localization to dendrites (Zempel et al., 2010).”
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“Indeed, calcium dyshomeostasis at the dendritic spine as well as altered mitochondrial activity have both been shown to induce dendritic spine loss (Zempel et al. 2010).”
BackgroundTangles, Toxicity, and Tau Secretion in AD – New Approaches to a Vexing Problem
Gendreau, K. L., & Hall, G. F. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00160 · Cited by 67
AMPA Receptor Trafficking in Natural and Pathological Aging
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“Particularly, hyperphosphorylated tau, but not a phosphorylation-deficient tau, is accumulated in dendritic spines where can dysregulate AMPAR trafficking together with key signaling molecules (Hoover et al., 2010; Zempel et al., 2010).”
BackgroundThe Emergence of NMDA Receptor Metabotropic Function: Insights from Imaging
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“the accumulation of Aβ exacerbates Tau’s pathology [6,55,56].”
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Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease
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“Similarly, expression of truncated versions of tau that lack dendritic localization has beneficial effects in APPswe transgenic mice (Ittner et al., 2010), fitting with evidence that shows the amyloid-β-induced mis-localization of endogeneous tau into dendrites is detrimental (Zempel et al., 2010).”
BackgroundMetformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice
Oliveira, W. H., Braga, C. F., Lós, D. B., Araújo, S. M. R., França, M. R., Duarte-Silva, E., Rodrigues, G. B., Rocha, S. W. S., & Peixoto, C. A. (2021) · Experimental Brain Research · doi:10.1007/s00221-021-06176-8 · Cited by 64
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“Excess dendritic tau has been implicated in synaptotoxicity mediated by NMDA receptors [52], and is potentiated by tau acetylation [53] Movement of tau into dendrites has also been reported by others in a small fraction of cultured neurons exposed to A oligomers (A Os) [54].”
Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease
Yan, R., Fan, Q., Zhou, J., & Vassar, R. J. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.025 · Cited by 71
“…2+ either in pre- or postsynaptic zones cause activation of calpain, which can lead to activation of cdk5 for Tau hyperphosphorylation and mis-sorting of endogenous Tau into dendrites, as well as pronounced depletion of microtubules and mitochondria (Frandemiche et al., 2014; Zempel et al., 2010).”
Hyperphosphorylated Tau is Elevated in Alzheimer's Disease with Psychosis
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“However, while it is appreciated that A drives missorting and phosphorylation of tau [50] and that reducing tau mitigates effects of A [29], it is unclear how the ratio of A isoforms may influence tau pathology.”
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“Furthermore, newly synthesized tau leads to the breakdown of dendritic microtubules, mitochondria mislocalization, and depletion of dendritic spines [14 ,15].”
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“Several groups have demonstrated that the neurotoxicity seen with different oligomer preparations is associated with tau phosphorylation [87–89].”
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“More recently, it has been shown that Aβ oligomers cause abnormal tau phosphorylation and morphology changes of spines by missorting of endogenous tau into dendrites [81].”
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“Recent studies in cultured neurons also implicate Aβ-induced increases in tau phosphorylation as the harbinger of Aβ-related neuritic pathology (30,31), and our data support this notion.”
ResultPowering Amyloid Beta Degrading Enzymes: A Possible Therapy for Alzheimer’s Disease
Sikanyika, N. L., Parkington, H. C., Smith, A. I., & Kuruppu, S. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02756-x · Cited by 79
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Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity
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“MT integrity has been implicated in dendritic spine density and morphology, synaptic plasticity, and memory formation (Fanara et al., 2010; Zempel et al., 2010; Atarod et al., 2015), but the precise role of MT stability and dynamics in synaptotoxicity is still controversial.”
InfluentialRole of Tau Protein in Neuronal Damage in Alzheimer's Disease and Down Syndrome
Cárdenas, A. M., Ardiles, Á. O., Barraza, N., Báez‐Matus, X., & Caviedes, P. A. (2012) · Archives of Medical Research · doi:10.1016/j.arcmed.2012.10.012 · Cited by 68
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“Tau localization to dendrites has also been identified, and is impacted by Aβ oligomers (Zempel et al., 2010).”
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A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers
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“Numerous adverse effects of A b Os on neurons are known to require tau (Zempel et al , 2010; DuBoff et al , 2012; Bloom, 2014), and pathological forms of tau can cause mitochondrial dysfunction (Zempel et al , 2010; DuBoff et al , 2012; Bloom, 2014).”
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Distribution of endogenous normal tau in the mouse brain
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“Furthermore, tau is also known to be mislocalized to synapses in AD, thus contributing to cognitive dysfunction (Zempel et al., 2010).”
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“Aβ can alter and depress synaptic function through mechanisms that involve NMDAR trafficking [37], tau mislocalization into dendritic spines [38,39], and a host of other mechanisms (reviewed in [10,40]) that may ultimately lead to network destabilization and cognitive dysfunction (reviewed in [9,10,40]).”
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“It has been suggested that Aβ oligomers induce tau missorting from axons to dendrites [37, 38].”
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“Tau phosphorylation has been correlated with detrimental effects at synapses in both AD and tauopathy transgenic mice (Bittner et al., 2010; Hoover et al., 2010; Steinhilb et al., 2007; Zempel et al., 2010).”
BackgroundProgress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?
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“Ab-normally phosphorylated tau proteins are more prone to aggregate to form neurofibrillary tangles, which are neurotoxic and can further damage neurons [142].”
Shea, D. W., Colasurdo, E. A., Smith, A. S. T., Paschall, C. J., Jayadev, S., Keene, C. D., Galasko, D. R., Ko, A. L., Li, G., Peskind, E. R., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2213157119 · Cited by 61
Kumar, P., Jha, N. K., Jha, S. K., Ramani, K., & Ambasta, R. K. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140933 · Cited by 67
“…pS46, and pS214, and finally the extra-NFT stage, characterized by substantial filamentous structures, was confirmed using the antibodies AT8 (pS199/pS202/pT205) AT100 (pT212/pS214), and PHF-1 (pS396/pS404) pattern of tau hyperphosphorylation that corresponds to the degree of AD pathology [99, 100].”
Smith, L. A., & McMahon, L. L. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.11.014 · Cited by 45
“…being elucidated, it is thought that elevated soluble Aβ leads to downstream tau hyperphosphorylation and mislocalization to somatodendritic comparments where it drives Aβ-induced downregulation of surface AMPARs (Hoover et al., 2010; Ittner et al., 2010; Miller et al., 2014; Zempel et al., 2010).”
InfluentialMAPping out distribution routes for kinesin couriers
Atherton, J., Houdusse, A., & Moores, C. A. (2013) · Biology of the Cell · doi:10.1111/boc.201300012 · Cited by 54
“Furthermore, tau is in fact lost from axons and redistributed to the somato-dendritic compartment, implying that other, axonally localised factors are responsible for the reduced axonal transport rates found in AD and the tauopathies (Kowall and Kosik, 1987; Zempel et al., 2010; Ittner and Gotz, 2011).”
BackgroundBrief update on different roles of tau in neurodegeneration
Ittner, A., Ke, Y. D., van Eersel, J., Gladbach, A., Götz, J., & Ittner, L. M. (2011) · IUBMB Life · doi:10.1002/iub.467 · Cited by 49
“Furthermore, Ab has been found to induce the accumulation of tau and other cytoskeletal proteins in a small subset of cells in primary neuronal cultures (100).”
BackgroundHarnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins
Chadarevian, J. P., Davtyan, H., Chadarevian, A. L., Nguyen, J., Capocchi, J. K., Le, L., Escobar, A., Chadarevian, T., Mansour, K., Deynega, E., et al. (2025) · Cell Stem Cell · doi:10.1016/j.stem.2025.03.009 · Cited by 60
Early Improved and Late Defective Cognition Is Reflected by Dendritic Spines in Tau.P301L Mice
Kremer, A., Maurin, H., Demedts, D., Devijver, H., Borghgraef, P., & LEUVEN, F. V. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4859-11.2011 · Cited by 50
“…contribution of protein Tau to the transport of the Src-kinase Fyn to the postsynaptic density under normal physiological conditions, but add considerable weight to the potential importance of protein Tau-Fyn interactions in pathology (Lee et al., 1998; Ittner et al., 2010; Zempel et al., 2010).”
BackgroundLaClair, K. D., Donde, A., Ling, J. P., Jeong, Y. H., Chhabra, R., Martin, L. J., & Wong, P. C. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1637-y · Cited by 76
“Importantly, we identified three pathways strongly implicated in the pathogenesis of AD that are also affected by cryptic exon incorporation in cT mice: synaptic signaling [18, 58], mitochondrial function [68, 70], and autophagy [45] (Table 1).”
Nevado‐Holgado, A. J., Ribé, E. M., Thei, L., Furlong, L. I., Mayer, M. Á., Quan, J., Richardson, J. C., Cavanagh, J., & Lovestone, S. (2019) · Cells · doi:10.3390/cells8050425 · Cited by 51
Tau Spreading Mechanisms; Implications for Dysfunctional Tauopathies
Fuster-Matanzo, A., Hernández, F., & Ávila, J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030645 · Cited by 50
“First, hyperphosphorylation of tau might induce tau missorting from axons to the somatodendritic compartment, which can cause synaptic dysfunction [32,33].”
BackgroundTong, M., Arora, K., White, M. M., & Nichols, R. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.241299 · Cited by 48
Xia, D., Gutmann, J. M., & Götz, J. (2016) · Scientific Reports · doi:10.1038/srep29074 · Cited by 47
Memory deficits correlate with tau and spine pathology in P 301 S MAPT transgenic mice
Xu, H. W., Rösler, T. W., Carlsson, T., de Andrade, A., Bruch, J., Höllerhage, M., Oertel, W. H., & Höglinger, G. U. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12160 · Cited by 60
Messing, L., Decker, J. M., Joseph, M., Mandelkow�, E., & Mandelkow, E.-M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.10.024 · Cited by 48
“Mislocalized tau was already present in dendritic spines at an early time point, similar to observations in primary neuronal cell culture (Hoover et al., 2010; Thies and Mandelkow, 2007; Zempel et al., 2010).”
BackgroundResultInfluentialSelf-citationNoradrenaline in the aging brain: Promoting cognitive reserve or accelerating Alzheimer's disease?
Mather, M. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.05.013 · Cited by 57
Calvo-Rodríguez, M., García-Durillo, M., Villalobos, C., & Núñez, L. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151189 · Cited by 50
“The death target and mechanism of Ca2+ entry induced by A 42 oligomers remain controversial [10, 11].”
Aβ Influences Cytoskeletal Signaling Cascades with Consequences to Alzheimer’s Disease
Henriques, A. G., Oliveira, J. M., Carvalho, L., & Silva, O. A. B. D. C. E. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8913-4 · Cited by 45
“MARK target sites in hippocampal neurons [114].”
The myriad roles of Miro in the nervous system: axonal transport of mitochondria and beyond
Lee, K., & Lu, B. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00330 · Cited by 46
“, and activation of the PAR-1/MARK-tau pathway has been observed in AD subjects and animal models (Chin et al., 2000; Wang et al., 2007; IijimaAndo et al., 2009; Zempel et al., 2010; Yu et al., 2012).”
BackgroundEffect Size of Memory Deficits in Mice with Adult-Onset P301L Tau Expression
Hunsberger, H. C., Rudy, C. C., Weitzner, D., Zhang, C., Tosto, D. E., Knowlan, K., Xu, Y., & Reed, M. N. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.06.057 · Cited by 46
Saito, T., Oba, T., Shimizu, S., Asada, A., Iijima, K., & Ando, K. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz120 · Cited by 51
Ahmed, T., Zahid, S., Mahboob, A., & Farhat, S. M. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160325121145 · Cited by 60
“According to the first hypothesis, physiological forms of tau may cause abnormal neural network activity via diverse pathogenic triggers [180, 181], while the second hypothesis proposed that the Aβ might change the PTM or distribution of tau, making it an active mediator of Aβ-induced neuronal dysfunction [182].”
A Lifespan Observation of a Novel Mouse Model: In Vivo Evidence Supports Aβ Oligomer Hypothesis
Zhang, Y., Lu, L., Jia, J., Jia, L., Geula, C., Pei, J.-J., Xu, Q., Qin, W., Liu, R., Li, D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085885 · Cited by 40
Tau Causes Synapse Loss without Disrupting Calcium Homeostasis in the rTg4510 Model of Tauopathy
Kopeikina, K. J., Wegmann, S., Pitstick, R., Carlson, G. A., Bacskai, B. J., Betensky, R. A., Hyman, B. T., & Spires‐Jones, T. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080834 · Cited by 48
“Studies of tau over-expressing neurons in culture have linked dendritic spine loss, the leading correlate to cognitive decline in AD [1,2,20], to alterations in calcium handling and mitochondrial mislocalization [12].”
BackgroundInfluentialChronic pain causes Tau-mediated hippocampal pathology and memory deficits
Guerreiro, S. R., Guimarães, M. R., Silva, J., Dioli, C., Vamvaka-Iakovou, A., Sousa, R., Gomes, P. A., Megalokonomou, A., Campos-Marques, C., Cunha, A. M., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01707-3 · Cited by 44
In vivo induction of membrane damage by β-amyloid peptide oligomers
Julien, C., Tomberlin, C., Roberts, C. M., Akram, A., Stein, G. H., Silverman, M. A., & Link, C. D. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0634-x · Cited by 39
Detection and Quantification of β-Amyloid, Pyroglutamyl Aβ, and Tau in Aged Canines
Schmidt, F., Boltze, J., Jäger, C., Hofmann, S., Willems, N., Seeger, J., Härtig, W., & Stolzing, A. (2015) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000230 · Cited by 87
Sahara, N., Murayama, M., Higuchi, M., Suhara, T., & Takashima, A. (2014) · Frontiers in Neurology · doi:10.3389/fneur.2014.00026 · Cited by 37
Zhang, T., Xia, Y., Hu, L., Chen, D., Gan, C., Wang, L., Mei, Y., Lan, G., Shui, X., Tian, Y., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.66760 · Cited by 46
“For instance, Aβ oligomers may activate protein kinases such as glycogen synthase kinase-3β (GSK-3β), Ca2+-dependent calmodulin kinase IIα (CaMKIIα) and cyclin-dependent kinase 5 (CDK5) that are able to directly phosphorylate tau proteins at AD-related sites [7-9].”
BackgroundExtracellular heat shock proteins in neurodegenerative diseases: New perspectives
Lyon, M. S., & Milligan, C. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134462 · Cited by 49
Calcium Signaling Deficits in Glia and Autophagic Pathways Contributing to Neurodegenerative Disease
Mustaly-Kalimi, S., Littlefield, A. M., & Stutzmann, G. E. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7266 · Cited by 47
“The accumulated s disrupts autophagic function and further dysregulates s clearance (5, 79, 198).”
Ando, K., Oka, M., Ohtake, Y., Motoki, H., Shimizu, S., Hisanaga, S., & Iijima, K. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.053 · Cited by 40
“The level of active MARKs is increased by β-amyloid, which is thought to be the primary causative agent of AD pathology and to act upstream of tau toxicity [23, 24, 34].”
Gan, K. J., & Silverman, M. A. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-12-1612 · Cited by 41
“Furthermore, cultured neurons treated with AβOs recapitulate AD pathologies such as calcium dyshomeostasis, kinase signaling cascade dysregulation, tau hyperphosphorylation, and FAT defects (De Felice et al., 2007, 2008; Decker et al., 2010b; Vossel et al., 2010; Zempel et al., 2010), which are central to this study.”
Alzheimer’s disease: a review on the current trends of the effective diagnosis and therapeutics
Manap, A. S. A., Almadodi, R., Sultana, S., Sebastian, M. G., Kavani, K. S., Lyenouq, V. E., & Shankar, A. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1429211 · Cited by 66
Hensley, K., Gabbita, S. P., Venkova, K. M., Hristov, A. M., Johnson, M. F., Eslami, P., & Harris‐White, M. E. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182a74372 · Cited by 44
Boehm, J. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12251 · Cited by 41
“Hyperphosphorylated tau was found to mislocalise from the axon toward dendrites and spines (Zempel et al., 2010), which places it close to the postsynaptic site of action.”
BackgroundGuan, P.-P., Cao, L., Yang, Y., & Wang, P. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.757515 · Cited by 47
“Based on this hypothesis, previous studies have shown that Ca2+ influx increases the production and aggregation of Aβ and the phosphorylated tau protein, which affects the learning and memory of patients with AD (Etcheberrigaray et al., 1998; Zempel et al., 2010; Tong et al., 2018).”
BackgroundUnderstanding Miro GTPases: Implications in the Treatment of Neurodegenerative Disorders
Kay, L., Pienaar, I. S., Cooray, R., Black, G. W., & Soundararajan, M. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0927-x · Cited by 44
Tau Mislocation in Glucocorticoid-Triggered Hippocampal Pathology
Pinheiro, S., Silva, J. M., Mota, C., Vaz‐Silva, J., Veloso, A., Pinto, V., Sousa, N., Cerqueira, J., & Sotiropoulos, I. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9356-2 · Cited by 47
“A previous study demonstrated that local Tau missorting induced by Aβ or glutamate was followed by local spine loss and cytoskeletal disruption [24]; importantly, this Tau mislocation at synapses are shown to depend on Tau hyperphosphorylation [19, 34].”
Beta-Amyloid and Tau-Protein: Structure, Interaction, and Prion-Like Properties
Tatarnikova, O. G., Орлов, М. А., & Bobkova, N. V. (2015) · Biochemistry (Moscow) · doi:10.1134/s000629791513012x · Cited by 62
“Pathological phosphorylation of Tau protein can be caused by activation of protein kinases dependent on Aβ, in particular GSK3 [74, 113, 114].”
BackgroundHaußmann, U., Jahn, O., Linning, P., Janßen, C., Liepold, T., Portelius, E., Zetterberg, H., Bauer, C., Schuchhardt, J., Knölker, H., et al. (2013) · Analytical Chemistry · doi:10.1021/ac401055y · Cited by 42
ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease
Krafft, G. A., Jerecı̀ć, J., Siemers, E., & Cline, E. N. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.848215 · Cited by 54
“…leads to loss of synapses and progressive neurodegeneration (Gong et al., 2003; De Felice et al., 2008; Krafft and Klein, 2010; Ondrejcak et al., 2010; Zempel et al., 2010; Klyubin et al., 2012; Koffie et al., 2012; Hayden and Teplow, 2013; Hefti et al., 2013; Fowler et al., 2014; Goure et al.,…”
BackgroundBalmik, A. A., & Chinnathambi, S. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170900 · Cited by 69
Golovyashkina, N., Penazzi, L., Ballatore, C., Smith, A. B., Bakota, L., & Brandt, R. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0049-0 · Cited by 41
“While the development of spine changes and neuron loss has been addressed in various animal and culture models [4–7], much less is known about how changes in dendritic complexity are mediated.”
Zherebitskaya, E., Schapansky, J., Akude, E., Smith, D. R., der Ploeg, R. V., Solovyova, N. A., Verkhratsky, A., & Fernyhough, P. (2011) · ASN NEURO · doi:10.1042/an20110038 · Cited by 37
Qi, P., Li, J., Gao, S., Yuan, Y., Sun, Y., Liu, N., Li, Y., Wang, G., Ling, C., & Shi, J. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.589588 · Cited by 49
“In addition, the accumulation of MAPT in dendrites is a critical step in Aβ-induced neurotoxicity (Ittner et al., 2010; Zempel et al., 2010).”
BackgroundOba, T., Saito, T., Asada, A., Shimizu, S., Iijima, K., & Ando, K. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014420 · Cited by 44
Arendash, G. W., Cao, C., Abulaban, H., Baranowski, R., Wisniewski, G., Becerra, L. R., Andel, R., Lin, X., Zhang, X., Wittwer, D., et al. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190367 · Cited by 52
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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