Tracy TE, Sohn PD, Minami SS, Wang C, Min SW, Li Y, Zhou Y, Le D, Lo I, Ponnusamy R, Cong X, Schilling B, Ellerby LM, Huganir RL, Gan L. Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss. Neuron. 2016 Apr 20;90(2):245-60. Epub 2016 Mar 31 PubMed.

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  1. Tau is mainly an axonal protein. However, it is also present at dendritic spines and it may play a toxic role there in Alzheimer’s disease and other tauopathies. That toxic role could be the consequence of tau modifications, such asphosphorylation, truncation, or acetylation. The role of acetylated tau in tauopathies is increasingly better understood. Tracy et al. describe, in an elegant manner, a possible mechanism for the role of acetylated tau (at lysines 274 and 281) in memory impairment using a mouse model overexpressing human tau with lysine to glutamine mutations to mimic lysine acetylation. Acetylated tau reduced the levels of kidney- and brain-expressed protein (KIBRA), a protein enriched in the postsynaptic density, and associated with late-onset sporadic AD. The mouse model data agreed with that finding, using AD patient samples. Thus, reduced KIBRA levels in AD patients with severe dementia was associated with enhanced acetylation of tau. Interestingly, increasing KIBRA levels in cultured hippocampal neurons from the transgenic mice corrected observed tau-mediated deficits in synaptic plasticity.

    As the authors suggest, the next steps will be to determine precisely how acetylated tau decreases KIBRA levels, and more precisely clarify whether or not direct binding between acetylated tau and KIBRA exists, as has been previously described for tau and fyn kinase in dendrites (Ittner et al., 2010). The role played by actin, while analyzed in this manuscript, should also be studied in more depth. Recently, it was demonstrated using an optogenic approach that strengthening neuronal connections restores spine density and long-term memory in a PS1/APP AD mouse model (Roy et al., 2016). It would be interesting to see if the same occurs in this AD model based on overexpressing pseudoacetylated tau.

    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.

    Roy DS, Arons A, Mitchell TI, Pignatelli M, Ryan TJ, Tonegawa S. Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease. Nature. 2016 Mar 24;531(7595):508-12. Epub 2016 Mar 16 PubMed.

    View all comments by Jesus Avila

  2. Finding acetylated tau at K-174 or 274 or 280 and/or at 281 in the CSF of AD patients versus control subjects free of cognitive issues will add more credence to the theory that acetylated tau is the missing link. If one can find such acetylated tau (which are at the microtubular domain binding region of tau) in the CSF of humans with AD and not in healthy controls, it will be a very important finding furthering the theory of post-translationally modified acetylated tau being a very early/upstream event in the pathogenesis of AD. We are currently conducting such a study at our center.

    View all comments by Joel Ross

  3. Although correlative studies strongly support associations between hyperphosphorylated tau, tangles, and AD symptoms (Tremblay et al., 2007; Bennett et al., 2004; Ghoshal et al., 2002), investigations in animals have not yet confirmed how tau acquires its pathogenicity. Post-translational modifications, which may lead to conformational changes and aggregation, have been pointed out, including not only phosphorylation, but also glycosylation (Zhu et al., 2014) and acetylation (Min et al., 2015; Irwin et al., 2013; Kingwell, 2015). 

    In this nice paper, Tracy et al. follow up their group’s recent publication in Nature Neuroscience (Min et al., 2015) on the role of acetylation in tau pathogenicity, this time attempting to better define causal mechanisms using transgenic mice expressing human tau with lysine-to-glutamine mutations at K274 and K281 (tauKQ) to mimic acetylation. Interestingly, reductions in tau phosphorylated at Ser202/Thr205 and to a lesser degree at Ser396/Ser404 were observed in tauKQ mice. Their main finding, however, is that mimicking acetylation of tau at two sites impairs synaptic plasticity and memory retention, which complements well the observations made in AD brains. Indeed, tau acetylation was found to appear early in the disease, particularly for ac-K281, at least based on clinical dementia ratings and Braak scores. However, more detailed correlative studies with different tau phospho-epitopes retrieved in soluble/insoluble fractions and antemortem cognitive symptoms would probably help better define the role of tau acetylation in the disease.

    Among mechanisms downstream of tau acetylation proposed by the authors, they identify a disruption of signaling pathways related to postsynaptic kidney/brain (KIBRA) protein which is well known for its role in synaptic plasticity and episodic memory, based on initial genetic studies (Milnik et al., 2012; Papassotiropoulos et al., 2006; Blanque et al., 2015). Incidentally, KIBRA modulators have been under development as cognitive enhancers by Sygnis Pharma for a few years (Pogacić Kramp and Herrling, 2009). A nice connection is also made with sirtuins, which are known for their deacetylase activity in vivo. A reduction of SIRT1 has been reported in AD brains, correlating with the accumulation of insoluble tau (Julien et al., 2009). Re-establishing SIRT1 activity could thus provide a means to correct the hyperacetylation of tau.

    There is no question that this kind of study is the loom upon which we will ultimately weave our understanding of tauopathies. Whether acetylation is more pathogenic than other post-translational alterations and whether reducing tau acetylation at lysine 274 or 281 is a viable therapeutic strategy, however, remain to be determined.

    References:

    Tremblay C, Pilote M, Phivilay A, Emond V, Bennett DA, Calon F. Biochemical characterization of Abeta and tau pathologies in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2007 Dec;12(4):377-90. PubMed.

    Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004 Mar;61(3):378-84. PubMed.

    Ghoshal N, García-Sierra F, Wuu J, Leurgans S, Bennett DA, Berry RW, Binder LI. Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer's disease. Exp Neurol. 2002 Oct;177(2):475-93. PubMed.

    Zhu Y, Shan X, Yuzwa SA, Vocadlo DJ. The emerging link between O-GlcNAc and Alzheimer disease. J Biol Chem. 2014 Dec 12;289(50):34472-81. Epub 2014 Oct 21 PubMed.

    Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, Sohn PD, Schilling B, Cong X, Ellerby L, Gibson BW, Johnson J, Krogan N, Shamloo M, Gestwicki J, Masliah E, Verdin E, Gan L. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015 Oct;21(10):1154-62. Epub 2015 Sep 21 PubMed.

    Irwin DJ, Cohen TJ, Grossman M, Arnold SE, McCarty-Wood E, Van Deerlin VM, Lee VM, Trojanowski JQ. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am J Pathol. 2013 Aug;183(2):344-51. PubMed.

    Kingwell K. Neurodegenerative disease: Targeting tau acetylation attenuates neurodegeneration. Nat Rev Drug Discov. 2015 Nov;14(11):748. PubMed.

    Milnik A, Heck A, Vogler C, Heinze HJ, de Quervain DJ, Papassotiropoulos A. Association of KIBRA with episodic and working memory: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2012 Dec;159B(8):958-69. Epub 2012 Oct 12 PubMed.

    Papassotiropoulos A, Stephan DA, Huentelman MJ, Hoerndli FJ, Craig DW, Pearson JV, Huynh KD, Brunner F, Corneveaux J, Osborne D, Wollmer MA, Aerni A, Coluccia D, Hänggi J, Mondadori CR, Buchmann A, Reiman EM, Caselli RJ, Henke K, de Quervain DJ. Common Kibra alleles are associated with human memory performance. Science. 2006 Oct 20;314(5798):475-8. PubMed.

    Blanque A, Repetto D, Rohlmann A, Brockhaus J, Duning K, Pavenstädt H, Wolff I, Missler M. Deletion of KIBRA, protein expressed in kidney and brain, increases filopodial-like long dendritic spines in neocortical and hippocampal neurons in vivo and in vitro. Front Neuroanat. 2015;9:13. Epub 2015 Feb 20 PubMed.

    Pogacić Kramp V, Herrling P. List of drugs in development for neurodegenerative diseases: update June 2009. Neurodegener Dis. 2009;6(4):165-212. PubMed.

    Julien C, Tremblay C, Emond V, Lebbadi M, Salem N, Bennett DA, Calon F. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol. 2009 Jan;68(1):48-58. PubMed.

    View all comments by Frederic Calon

  4. The molecular mechanisms of long-term memory can be divided into two mechanistically distinct phases—induction and maintenance. Induction is a transient period of cellular consolidation lasting an hour or two, in which short-term memories are converted into long-term memories. Maintenance is the persistent phase of memory storage, lasting days to weeks to months and even longer. Which phase of memory does Alzheimer’s disease disrupt? Most neuroscientists would say induction. In part, this is because there are hundreds of molecules that have been implicated in induction, including NMDA receptor, CaMKII, PKA, ERK, mTOR, CREB, and the GluA1 subunit of the AMPA receptor, many of which are altered in the brains of individuals with Alzheimer’s disease or in animal models of the disorder. In contrast, only very few molecules have been implicated in maintaining long-term memory storage.

    An important finding of Tracy et al. is that pathophysiologically altered tau, a hallmark of Alzheimer’s disease, might directly disrupt the persistence of memory through downregulation of one of these key maintenance molecules. A leading hypothesis for the molecular mechanism of long-term memory storage is the persistent action of the autonomously active PKC isoform, PKMζ, whose sustained phosphorylation maintains an increased number of GluA2 subunit-containing AMPARs at postsynaptic sites. The key molecule linking PKMζ to GluA2 is KIBRA, which directly binds both molecules.

    Tracy et al. present data suggesting that in Alzheimer’s disease, abnormally acetylated tau disrupts the function of KIBRA, suppressing both long-term potentiation and long-term memory. Thus, the abnormally acetylated tau disconnects PKMζ, the biochemical mechanism of memory maintenance, from its target, the AMPARs that mediate functional modifications in neural circuits. If further work supports this hypothesis, this would mean that the tau-mediated pathology of Alzheimer’s strikes at the very essence of long-term memory storage.

    View all comments by Todd Sacktor

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