Frandemiche ML, De Seranno S, Rush T, Borel E, Elie A, Arnal I, Lanté F, Buisson A.
Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers.
J Neurosci. 2014 Apr 23;34(17):6084-97.
PubMed.
This is a very interesting and elegant study that adds support for the idea that tau is normally present in dendrites and plays a physiological role in normal synaptic functioning. The movement of tau into spines with neuronal activity is demonstrated in both dissociated cultured neurons and hippocampal slices, and by both imaging and biochemical approaches. The implications of this change in tau localization, and its effects on postsynaptic function, will be an important focus for future studies. It seems unlikely that this postsynaptic tau plays a critical role in long-term potentiation (LTP), given that multiple studies have found that tau knockout mice have normal hippocampal LTP (Roberson et al., 2011; Shipton et al., 2011). However, postsynaptic tau in spines may play a role in controlling susceptibility to hyperexcitation and epileptiform activity and/or in regulating long-term depression, both of which are altered in tau knockout mice (Roberson et al., 2007, 2011; Ittner et al., 2011; Holth et al., 2013; DeVos et al., 2013; Kimura et al., 2013).
Tau in spines may also play an important role in disease, of course. Another interesting aspect of this study is the proposition that there are differences between the tau translocation into spines induced by Aβ and the tau translocation into spines induced by synaptic activity. This suggests that tau in spines is detrimental only under certain circumstances, and it will be important to further elucidate the differences between physiological and pathological tau in spines.
References:
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L.
Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.
J Neurosci. 2011 Jan 12;31(2):700-11.
PubMed.
Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, Dawson HN, Vitek MP, Wade-Martins R, Paulsen O, Vargas-Caballero M.
Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation.
J Neurosci. 2011 Feb 2;31(5):1688-92.
PubMed.
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L.
Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model.
Science. 2007 May 4;316(5825):750-4.
PubMed.
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L.
Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.
J Neurosci. 2011 Jan 12;31(2):700-11.
PubMed.
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J.
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.
Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22
PubMed.
Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L, Younkin SG, Pautler RG, Botas J, Noebels JL.
Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy.
J Neurosci. 2013 Jan 23;33(4):1651-9.
PubMed.
Devos SL, Goncharoff DK, Chen G, Kebodeaux CS, Yamada K, Stewart FR, Schuler DR, Maloney SE, Wozniak DF, Rigo F, Bennett CF, Cirrito JR, Holtzman DM, Miller TM.
Antisense Reduction of Tau in Adult Mice Protects against Seizures.
J Neurosci. 2013 Jul 31;33(31):12887-97.
PubMed.
Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K.
Microtubule-associated protein tau is essential for long-term depression in the hippocampus.
Philos Trans R Soc Lond B Biol Sci. 2014 Jan 5;369(1633):20130144. Print 2014 Jan 5
PubMed.
I enjoyed reading this paper. The study adds to the notion that a prime function of tau is that of a scaffolding protein, not only in the axon but also in the dendrite where tau interacts, as this study shows, also with filamentous actin. Interesting is the role specific phosphorylation reactions have in activity—and Aβ-dependent tau localization. While tau is often perceived as being either normally phosphorylated or hyperphosphorylated, this study underscores the notion that there is a physiological role for distinct phosphorylation sites (see Fig. 9). I am convinced that the future will see many more studies into tau trafficking and how it is regulated by site-specific phosphorylation.
This study from the Buisson lab adds more data arguing that tau may contribute to the regulation of synaptic plasticity. It has long been known that tau can bind to f-actin, particularly when phosphorylated at the KXGS-motifs (Mandelkow et al., 2004; Whiteman et al., 2009), and that it can enter spines when overexpressed (Thies et al., 2007; Zempel et al., 2013). When the authors activate synapses or add jasplakinolide, a substance that increases the f-actin content, more tau invades the spines, presumably because the spine volume and f-actin content increase.
The interesting part is the potential regulation of this process, which may rely on phosphorylation: The lab of Kwangwook Cho at the University of Bristol, England, has previously shown that tau is essential for regulating long-term depression (LTD), an important form of plasticity, and that LTD comes along with phosphorylation of tau at the PHF-1 site (Kimura et al., 2014). When the authors of this study mutated tau on serine 404 (which is part of the PHF-1 epitope when phosphorylated) to alanine, tau did not enter spines anymore upon synaptic activation (but remained in the dendrite as a result of overexpression), indicating that this phosphorylation site might be important for tau to enter spines. Our studies have shown that tau can enter spines and greatly accumulates there when pseudophosphorylated at the KXGS-motifs (by mutating to KXGE), and that this leads to a disassembly of f-actin in spines and spine decay (Zempel et al., 2013). Thus, sequential or combined phosphorylation at the KXGS motifs (Zempel et al., 2013) and at S404/PHF-1 motif (Kimura et al., 2014; this paper) might enable tau to translocate into spines and cause LTD.
The majority of the Alzheimer’s research field would probably accept that dendritic tau is a pathological sign. Therefore the caveat of the study is that it is still a matter of debate whether endogenous tau plays a physiological role in dendrites and in spine plasticity. Tau is only present in significant amounts in dendrites when overexpressed (this paper) or when endogenous tau is pathologically missorted. Endogenous tau and in particular tau phosphorylated at the PHF-1 epitope predominantly resides in the axon, even in conditions that acutely induce pathological missorting of tau (Kaech and Banker, 2005; Zempel et al., 2010).
References:
Mandelkow EM, Thies E, Trinczek B, Biernat J, Mandelkow E.
MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons.
J Cell Biol. 2004 Oct 11;167(1):99-110.
PubMed.
Whiteman IT, Gervasio OL, Cullen KM, Guillemin GJ, Jeong EV, Witting PK, Antao ST, Minamide LS, Bamburg JR, Goldsbury C.
Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of alzheimer-like neuritic cytoskeletal striations.
J Neurosci. 2009 Oct 14;29(41):12994-3005.
PubMed.
Thies E, Mandelkow EM.
Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1.
J Neurosci. 2007 Mar 14;27(11):2896-907.
PubMed.
Zempel H, Luedtke J, Kumar Y, Biernat J, Dawson H, Mandelkow E, Mandelkow EM.
Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin.
EMBO J. 2013 Nov 13;32(22):2920-37.
PubMed.
Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K.
Microtubule-associated protein tau is essential for long-term depression in the hippocampus.
Philos Trans R Soc Lond B Biol Sci. 2014 Jan 5;369(1633):20130144. Print 2014 Jan 5
PubMed.
Zempel H, Thies E, Mandelkow E, Mandelkow EM.
Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines.
J Neurosci. 2010 Sep 8;30(36):11938-50.
PubMed.
The authors have published a clear and well-performed study on the role of dendritic tau. Several years ago, the dogma was that tau is an intracellular, axonal protein. Now, we know about the multiple faces of tau. Tau could be inside or outside a neuron, or located at the axon or the dendrites. To explain those different features, it has been suggested that different tau isoforms may play different functions (Ittner et al., 2011; Liu and Götz., 2013). Focusing on dendritic tau, the French team report that synaptic activation and Aβ induces translocation of tau to dendritic spines in different ways, and that this difference relates to tau phosphorylation profiles.
Previously, it was proposed that Aβ-induced tau phosphorylation changes the morphology or even ablates previously assembled spines (Merino-Serrais et al., 2013). This possibility should be further analyzed.
References:
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J.
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.
Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22
PubMed.
Liu C, Götz J.
Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus.
PLoS One. 2013;8(12):e84849. Epub 2013 Dec 30
PubMed.
Merino-Serrais P, Benavides-Piccione R, Blazquez-Llorca L, Kastanauskaite A, Rábano A, Avila J, Defelipe J.
The influence of phospho-τ on dendritic spines of cortical pyramidal neurons in patients with Alzheimer's disease.
Brain. 2013 Jun;136(Pt 6):1913-28.
PubMed.
Comments
University of Alabama at Birmingham
This is a very interesting and elegant study that adds support for the idea that tau is normally present in dendrites and plays a physiological role in normal synaptic functioning. The movement of tau into spines with neuronal activity is demonstrated in both dissociated cultured neurons and hippocampal slices, and by both imaging and biochemical approaches. The implications of this change in tau localization, and its effects on postsynaptic function, will be an important focus for future studies. It seems unlikely that this postsynaptic tau plays a critical role in long-term potentiation (LTP), given that multiple studies have found that tau knockout mice have normal hippocampal LTP (Roberson et al., 2011; Shipton et al., 2011). However, postsynaptic tau in spines may play a role in controlling susceptibility to hyperexcitation and epileptiform activity and/or in regulating long-term depression, both of which are altered in tau knockout mice (Roberson et al., 2007, 2011; Ittner et al., 2011; Holth et al., 2013; DeVos et al., 2013; Kimura et al., 2013).
Tau in spines may also play an important role in disease, of course. Another interesting aspect of this study is the proposition that there are differences between the tau translocation into spines induced by Aβ and the tau translocation into spines induced by synaptic activity. This suggests that tau in spines is detrimental only under certain circumstances, and it will be important to further elucidate the differences between physiological and pathological tau in spines.
References:
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011 Jan 12;31(2):700-11. PubMed.
Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, Dawson HN, Vitek MP, Wade-Martins R, Paulsen O, Vargas-Caballero M. Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci. 2011 Feb 2;31(5):1688-92. PubMed.
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011 Jan 12;31(2):700-11. PubMed.
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.
Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L, Younkin SG, Pautler RG, Botas J, Noebels JL. Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J Neurosci. 2013 Jan 23;33(4):1651-9. PubMed.
Devos SL, Goncharoff DK, Chen G, Kebodeaux CS, Yamada K, Stewart FR, Schuler DR, Maloney SE, Wozniak DF, Rigo F, Bennett CF, Cirrito JR, Holtzman DM, Miller TM. Antisense Reduction of Tau in Adult Mice Protects against Seizures. J Neurosci. 2013 Jul 31;33(31):12887-97. PubMed.
Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K. Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc Lond B Biol Sci. 2014 Jan 5;369(1633):20130144. Print 2014 Jan 5 PubMed.
The University of Queensland
I enjoyed reading this paper. The study adds to the notion that a prime function of tau is that of a scaffolding protein, not only in the axon but also in the dendrite where tau interacts, as this study shows, also with filamentous actin. Interesting is the role specific phosphorylation reactions have in activity—and Aβ-dependent tau localization. While tau is often perceived as being either normally phosphorylated or hyperphosphorylated, this study underscores the notion that there is a physiological role for distinct phosphorylation sites (see Fig. 9). I am convinced that the future will see many more studies into tau trafficking and how it is regulated by site-specific phosphorylation.
This study from the Buisson lab adds more data arguing that tau may contribute to the regulation of synaptic plasticity. It has long been known that tau can bind to f-actin, particularly when phosphorylated at the KXGS-motifs (Mandelkow et al., 2004; Whiteman et al., 2009), and that it can enter spines when overexpressed (Thies et al., 2007; Zempel et al., 2013). When the authors activate synapses or add jasplakinolide, a substance that increases the f-actin content, more tau invades the spines, presumably because the spine volume and f-actin content increase.
The interesting part is the potential regulation of this process, which may rely on phosphorylation: The lab of Kwangwook Cho at the University of Bristol, England, has previously shown that tau is essential for regulating long-term depression (LTD), an important form of plasticity, and that LTD comes along with phosphorylation of tau at the PHF-1 site (Kimura et al., 2014). When the authors of this study mutated tau on serine 404 (which is part of the PHF-1 epitope when phosphorylated) to alanine, tau did not enter spines anymore upon synaptic activation (but remained in the dendrite as a result of overexpression), indicating that this phosphorylation site might be important for tau to enter spines. Our studies have shown that tau can enter spines and greatly accumulates there when pseudophosphorylated at the KXGS-motifs (by mutating to KXGE), and that this leads to a disassembly of f-actin in spines and spine decay (Zempel et al., 2013). Thus, sequential or combined phosphorylation at the KXGS motifs (Zempel et al., 2013) and at S404/PHF-1 motif (Kimura et al., 2014; this paper) might enable tau to translocate into spines and cause LTD.
The majority of the Alzheimer’s research field would probably accept that dendritic tau is a pathological sign. Therefore the caveat of the study is that it is still a matter of debate whether endogenous tau plays a physiological role in dendrites and in spine plasticity. Tau is only present in significant amounts in dendrites when overexpressed (this paper) or when endogenous tau is pathologically missorted. Endogenous tau and in particular tau phosphorylated at the PHF-1 epitope predominantly resides in the axon, even in conditions that acutely induce pathological missorting of tau (Kaech and Banker, 2005; Zempel et al., 2010).
References:
Mandelkow EM, Thies E, Trinczek B, Biernat J, Mandelkow E. MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J Cell Biol. 2004 Oct 11;167(1):99-110. PubMed.
Whiteman IT, Gervasio OL, Cullen KM, Guillemin GJ, Jeong EV, Witting PK, Antao ST, Minamide LS, Bamburg JR, Goldsbury C. Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of alzheimer-like neuritic cytoskeletal striations. J Neurosci. 2009 Oct 14;29(41):12994-3005. PubMed.
Thies E, Mandelkow EM. Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J Neurosci. 2007 Mar 14;27(11):2896-907. PubMed.
Zempel H, Luedtke J, Kumar Y, Biernat J, Dawson H, Mandelkow E, Mandelkow EM. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013 Nov 13;32(22):2920-37. PubMed.
Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K. Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc Lond B Biol Sci. 2014 Jan 5;369(1633):20130144. Print 2014 Jan 5 PubMed.
Kaech S, Banker G. Culturing hippocampal neurons. Nat Protoc. 2006;1(5):2406-15. PubMed.
Zempel H, Thies E, Mandelkow E, Mandelkow EM. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci. 2010 Sep 8;30(36):11938-50. PubMed.
Universidad Autónoma de Madrid
The authors have published a clear and well-performed study on the role of dendritic tau. Several years ago, the dogma was that tau is an intracellular, axonal protein. Now, we know about the multiple faces of tau. Tau could be inside or outside a neuron, or located at the axon or the dendrites. To explain those different features, it has been suggested that different tau isoforms may play different functions (Ittner et al., 2011; Liu and Götz., 2013). Focusing on dendritic tau, the French team report that synaptic activation and Aβ induces translocation of tau to dendritic spines in different ways, and that this difference relates to tau phosphorylation profiles.
Previously, it was proposed that Aβ-induced tau phosphorylation changes the morphology or even ablates previously assembled spines (Merino-Serrais et al., 2013). This possibility should be further analyzed.
References:
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.
Liu C, Götz J. Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PLoS One. 2013;8(12):e84849. Epub 2013 Dec 30 PubMed.
Merino-Serrais P, Benavides-Piccione R, Blazquez-Llorca L, Kastanauskaite A, Rábano A, Avila J, Defelipe J. The influence of phospho-τ on dendritic spines of cortical pyramidal neurons in patients with Alzheimer's disease. Brain. 2013 Jun;136(Pt 6):1913-28. PubMed.
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