Bad Ac-etylated Tau
Authors: Jane C. Hettinger, John R. Cirrito
Journal: Neuron (2016)

By using a tau construct with two mimicked acetylation sites as identified in AD brains, Tracy et al., 2016Tracy T.E. Sohn P.D. Minami S.S. Wang C. Min S.W. Li Y. Zhou Y. Le D. Lo I. Ponnusamy R. et al.Neuron. 2016; 90 (this issue): 245-260Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar found that acetylated tau promotes synaptic dysfunction through disruption of postsynaptic KIBRA signaling pathways, actin dynamics, and AMPA receptor trafficking. By using a tau construct with two mimicked acetylation sites as identified in AD brains, Tracy et al., 2016Tracy T.E. Sohn P.D. Minami S.S. Wang C. Min S.W. Li Y. Zhou Y. Le D. Lo I. Ponnusamy R. et al.Neuron. 2016; 90 (this issue): 245-260Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar found that acetylated tau promotes synaptic dysfunction through disruption of postsynaptic KIBRA signaling pathways, actin dynamics, and AMPA receptor trafficking. Tauopathies are a group of neurodegenerative disorders characterized by the pathological aggregation of the microtubule-associated tau protein into neurofibrillary tangles (NFTs). The most common such disorder is Alzheimer's disease (AD), but there are more than 20 other disorders that fall under this pathological umbrella, including progressive supranuclear palsy and frontotemporal dementias (Williams, 2006Williams D.R. Intern. Med. J. 2006; 36: 652-660Crossref PubMed Scopus (180) Google Scholar). Despite the prevalence of neurofibrillary degeneration, the pathogenic role of tau accumulation in these disorders remains unclear. However, unlike amyloid accumulation, the level of tau aggregation correlates with the degree of cognitive decline in AD, suggesting a relationship between tau and synaptic transmission (Giannakopoulos et al., 2003Giannakopoulos P. Herrmann F.R. Bussière T. Bouras C. Kövari E. Perl D.P. Morrison J.H. Gold G. Hof P.R. Neurology. 2003; 60: 1495-1500Crossref PubMed Scopus (782) Google Scholar). Both aggregated and soluble tau have been linked to synaptic dysfunction through various mechanisms, including the disruption of postsynaptic structure (Crimins et al., 2013Crimins J.L. Pooler A. Polydoro M. Luebke J.I. Spires-Jones T.L. Ageing Res. Rev. 2013; 12: 757-763Crossref PubMed Scopus (114) Google Scholar). Though tau is most often considered a microtubule-binding protein, tau also directly interacts with actin and regulates its stability (Frandemiche et al., 2014Frandemiche M.L. De Seranno S. Rush T. Borel E. Elie A. Arnal I. Lanté F. Buisson A. J. Neurosci. 2014; 34: 6084-6097Crossref PubMed Scopus (177) Google Scholar, Fulga et al., 2007Fulga T.A. Elson-Schwab I. Khurana V. Steinhilb M.L. Spires T.L. Hyman B.T. Feany M.B. Nat. Cell Biol. 2007; 9: 139-148Crossref PubMed Scopus (362) Google Scholar). F-actin is well known for its role in dendritic spine morphology and postsynaptic reorganizations associated with synaptic plasticity (Hotulainen and Hoogenraad, 2010Hotulainen P. Hoogenraad C.C. J. Cell Biol. 2010; 189: 619-629Crossref PubMed Scopus (588) Google Scholar). Its interaction with actin, therefore, is one way that tau is situated to influence the structure and composition of the postsynaptic density. The tau protein undergoes a number of post-translational modifications that influence its function and its propensity to form aggregates. At least 100 sites within tau have been identified for post-translational modification; most often this is phosphorylation, though ubiquitination, O-GlucNAc modification, methylation, and acetylation occur as well (for review, see Morris et al., 2015Morris M. Knudsen G.M. Maeda S. Trinidad J.C. Ioanoviciu A. Burlingame A.L. Mucke L. Nat. Neurosci. 2015; 18: 1183-1189Crossref PubMed Scopus (310) Google Scholar). While tau hyperphosphorylation has emerged as the prominent pathological modification in AD, a growing number of studies have linked the acetylation of tau lysine residues to tau dysfunction and toxicity (for review, see Cook et al., 2014Cook C. Stankowski J.N. Carlomagno Y. Stetler C. Petrucelli L. Alzheimers Res. Ther. 2014; 6: 29Crossref PubMed Scopus (93) Google Scholar). The first evidence for tau acetylation and its role in neurodegeneration came in 2010, when Min et al. showed that acetylation slows the degradation of tau by precluding its ubiquitination and degradation by the proteasome. Since this finding, acetylated tau has been identified in every major human tauopathy except for argyrophilic grain disease (Grinberg et al., 2013Grinberg L.T. Wang X. Wang C. Sohn P.D. Theofilas P. Sidhu M. Arevalo J.B. Heinsen H. Huang E.J. Rosen H. et al.Acta Neuropathol. 2013; 125: 581-593Crossref PubMed Scopus (78) Google Scholar). Increased levels of tau acetylation have been seen in human brains even before the accumulation of tau tangles, marking it as an early event in disease pathology (Min et al., 2010Min S.W. Cho S.H. Zhou Y. Schroeder S. Haroutunian V. Seeley W.W. Huang E.J. Shen Y. Masliah E. Mukherjee C. et al.Neuron. 2010; 67: 953-966Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar). Acetylation of tau appears to alter its functioning in a variety of ways, including preventing tau degradation and clearance (Min et al., 2010Min S.W. Cho S.H. Zhou Y. Schroeder S. Haroutunian V. Seeley W.W. Huang E.J. Shen Y. Masliah E. Mukherjee C. et al.Neuron. 2010; 67: 953-966Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar), interfering with tau-mediated stabilization of microtubules (Cohen et al., 2011Cohen T.J. Guo J.L. Hurtado D.E. Kwong L.K. Mills I.P. Trojanowski J.Q. Lee V.M. Nat. Commun. 2011; 2: 252Crossref PubMed Scopus (479) Google Scholar), and promoting tau aggregation (Morris et al., 2015Morris M. Knudsen G.M. Maeda S. Trinidad J.C. Ioanoviciu A. Burlingame A.L. Mucke L. Nat. Neurosci. 2015; 18: 1183-1189Crossref PubMed Scopus (310) Google Scholar). This study by Tracy et al., 2016Tracy T.E. Sohn P.D. Minami S.S. Wang C. Min S.W. Li Y. Zhou Y. Le D. Lo I. Ponnusamy R. et al.Neuron. 2016; 90 (this issue): 245-260Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, in this issue of Neuron, is the first to investigate the role of acetylated tau in synaptic dysfunction, offering a novel mechanism through which tau acetylation is pathogenic. In the current study, Tracy and colleagues (Tracy et al., 2016Tracy T.E. Sohn P.D. Minami S.S. Wang C. Min S.W. Li Y. Zhou Y. Le D. Lo I. Ponnusamy R. et al.Neuron. 2016; 90 (this issue): 245-260Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar) analyzed tissue homogenate from both human AD brain and Tg4510 brain, a tauopathy mouse model. They identified two acetylation sites, one already established in AD brains (K274) and the other a novel finding (K281). By developing specific antibodies for these acetylation sites, they found that murine tau acetylation was elevated in tauWT (wild-type) mice overexpressing human amyloid precursor protein (hAPP), linking amyloid pathology to tau acetylation. The antibodies were also used in human brains, where they found much greater acetylation at these sites in the most severe dementia cases when compared to patients without cognitive impairment. Further, the levels of K281 acetylation were elevated in mildly demented cases, though K274 acetylation levels were unchanged. This presents the intriguing concept that the functional effect of acetylation on tau is site specific. In order to probe how acetylation is associated with cognitive decline, the researchers generated mice with human tau mutated at K274 and K281 with a lysine to glutamine substitution, thus mimicking acetylation at these sites. Two lines were established: tauKQ mice with similar levels of human and WT murine tau and tauKQhigh mice with higher levels of human tau. Both of these acetylation-mimic mice showed higher levels of misfolded tau, as identified by MC1 immunoreactivity. Functionally, hippocampal slices from tauKQ mice displayed impaired LTP (long-term potentiation), though basal synaptic transmission was unaffected. In behavioral tests, the tauKQ mice exhibited spatial memory deficits as well as impaired object-context discrimination. Using a subtle behavioral assay involving fear conditioning in two distinct but similar contexts, the authors showed that these mice have diminished ability to distinguish between similar memories, a function attributed to dentate granule neurons. This suggests that tau acetylation, specifically at these sites, impacts synaptic function and behavior. Having established a clear cognitive impairment in mice expressing tauKQ, the authors used primary hippocampal neurons transfected with either WT tau, tauKQ, or tau mutated to block acetylation (tauKR) in order to explore the molecular mechanism behind this dysfunction. The ability to mimic and block acetylation provides a powerful model for these studies. Though there were equivalent levels of GluA1 in the spines of neurons with tauWT, tauKQ, and tauKR, only neurons with mimicked acetylation (tauKQ) failed to increase the insertion of AMPA receptors (AMPARs) into the postsynaptic membrane following the chemical induction of LTP. In hippocampal slices, LTP was also impaired in tauKQ mice, and the activity-mediated increase in polymerized actin seen with tauWT mice was abolished. Importantly, an actin-stabilizing agent rescued this deficit. Finally, tauKQ did not coprecipitate with actin, though tauWT did. These data certainly suggest a relationship between tau acetylation, actin polymerization, and synaptic dysfunction, though the causative nature of this relationship has yet to be proven. Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms in the kidney/brain gene (KIBRA) associated with increased risk of late-onset AD and others associated with memory performance (Zhang et al., 2014Zhang L. Yang S. Wennmann D.O. Chen Y. Kremerskothen J. Dong J. Cell. Signal. 2014; 26: 1392-1399Crossref PubMed Scopus (45) Google Scholar). In animal models, reduction in levels of KIBRA results in impaired learning and memory, diminished LTP and LTD (long-term depression), and the aberrant trafficking of AMPARs during synaptic plasticity (Makuch et al., 2011Makuch L. Volk L. Anggono V. Johnson R.C. Yu Y. Duning K. Kremerskothen J. Xia J. Takamiya K. Huganir R.L. Neuron. 2011; 71: 1022-1029Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Due to its relationship with postsynaptic functioning, Tracy et al. (2016) assessed the levels of KIBRA in human AD brains. Like acetylated tau, they found that KIBRA levels were higher in severely impaired AD cases compared to cognitively normal cases. Though KIBRA levels were not altered in tauKQ mice, the authors did find that colocalization between KIBRA and actin was weaker in these animals. These findings suggest that KIBRA function and tau acetylation are related, but it remains unclear how these events are linked. Again turning to neuronal cultures to address mechanism, Tracy et al., 2016Tracy T.E. Sohn P.D. Minami S.S. Wang C. Min S.W. Li Y. Zhou Y. Le D. Lo I. Ponnusamy R. et al.Neuron. 2016; 90 (this issue): 245-260Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar transfected primary neurons with KIBRA, tauKQ, or both constructs. In neurons with tauKQ only, LTP induction did not result in AMPAR trafficking to the postsynaptic membrane, as is required for plasticity. However, neurons that contained either KIBRA or KIBRA with tauKQ exhibited normal AMPAR insertion following LTP induction. Thus, KIBRA is sufficient to restore normal AMPAR recruitment in synapses with acetylated tau. Because tau-mediated synaptic dysfunction has been linked to actin depolymerization and because KIBRA colocalization with actin is decreased in tauKQ mice, the authors analyzed actin levels in neurons with KIBRA and tauKQ. While activity-dependent actin polymerization is blocked in tauKQ-expressing neurons, this deficit is entirely rescued in neurons with both KIBRA and tauKQ. This is the first study to offer a mechanism by which KIBRA contributes to AD, in this case through acetylated tau. Previous studies have shown that KIBRA is linked to LTP and that KIBRA levels are reduced in AD brains (Zhang et al., 2014Zhang L. Yang S. Wennmann D.O. Chen Y. Kremerskothen J. Dong J. Cell. Signal. 2014; 26: 1392-1399Crossref PubMed Scopus (45) Google Scholar) but have yet to identify a mechanistic connection between AD pathology, KIBRA dysfunction, and impaired memory. Importantly, that tau affects KIBRA does not preclude KIBRA being related to other AD-related proteins as well, nor does it mean that the synaptic effect of tau is limited to KIBRA. Other synaptic targets could be involved as well, either directly or indirectly. One potential caveat of these studies is that though they focus on tau with altered acetylation, tau in vivo will still undergo other post-translational modifications. Is it possible that acetylation increases such modifications, which then have a synaptic effect, or that a permanent acetylation mimic prevents modifications that would otherwise have a beneficial effect? The current study by Tracy et al., 2016Tracy T.E. Sohn P.D. Minami S.S. Wang C. Min S.W. Li Y. Zhou Y. Le D. Lo I. Ponnusamy R. et al.Neuron. 2016; 90 (this issue): 245-260Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar is an outstanding first step in understanding how site-specific tau acetylation could impact an AD phenotype, but it is important that next steps cover tau acetylation and other modifications in a more comprehensive setting. This study adds to the growing evidence that post-translational modifications of tau, beyond phosphorylation, are critical to its role in cognitive deficits. Acetylation appears to be an important, early event in AD pathology, linking tau dysfunction with synaptic impairment. Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory LossTracy et al.NeuronMarch 31, 2016In BriefTracy et al. identify K274 and K281 acetylation on tau as a contributing factor to synaptic dysfunction and memory loss related to Alzheimer's disease. They show that acetylated tau disrupts postsynaptic signaling required for long-term synaptic strengthening. Full-Text PDF Open Archive