Ying Cheng
Feng Bai- 1Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China
- 2Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
Increasing evidence suggests that abnormally hyperphosphorylated tau plays a vital role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction also has a recognized role in the pathophysiology of AD. In recent years, mitochondrial dysfunction has been strongly associated with tau pathology in AD. Overexpression of hyperphosphorylated and aggregated tau appears to damage the axonal transport, leading to abnormal mitochondrial distribution. In addition, pathological tau impairs mitochondrial dynamics by regulating mitochondrial fission/fusion proteins, and further causes mitochondrial dysfunction and neuronal damage. Moreover, mitochondrial dysfunction is also involved in promoting tau pathology in AD. In this article, we evaluate the relationship between phosphorylated tau and mitochondrial dysfunction in AD.
Introduction
To determine the physiopathologic mechanism of AD for effective prevention and treatment, several modeling hypotheses have emerged, although the exact cause of AD is still unclear. Hardy and Higgins (1992) first formulated the amyloid hypothesis in 1992, which was widely accepted at the time but is much questioned now (Hardy and Selkoe, 2002). In the amyloid hypothesis, amyloid precursor protein (APP) is cleaved by β and γ-secretases and produces amyloid beta 42 (Aβ42) fragments. Aβ42 fragments aggregate into insoluble extracellular fibrils of neuritic plaques (NPs), and neurofibrillary tangles (NFTs) are subsequently formed. However, several molecular and genetic abnormalities and inconsistent clinical correlations identified in some research cannot be explained by this hypothesis. Furthermore, no new drug based on the amyloid hypothesis has been approved over the past decade. Recently, another phase III clinical trial of Alzheimer's drug targeting Aβ was shuttered because the drug has no chance of benefiting AD patients. Given the failures of the clinical trials based on the amyloid hypothesis, the tau hypothesis, an alternative pathway, is now attracting increasing attention. It is well-known that NFTs, which are composed primarily of hyperphosphorylated tau protein (Grundke-Iqbal et al., 1986; Nukina and Ihara, 1986), have been proposed as the second pathological hallmark of AD. In addition, increasing evidence suggests that abnormally hyperphosphorylated tau plays a vital role in the pathogenesis of AD. Hyperphosphorylated tau can lead to microtubule dysfunction, impair axonal transport of organelles including mitochondria, and result in synaptic dysfunction (Ittner and Götz, 2011; Cai and Tammineni, 2017). Mitochondrial dysfunction has been indicated as an underlying mechanism of AD pathophysiology. Accumulating evidence indicates a strong association of tau pathology with mitochondrial dysfunction in AD (Eckert et al., 2014). Overexpression and hyperphosphorylation of tau appear to impair mitochondrial axonal transportation, mitochondrial dynamics and function, and finally neuronal health (Eckert et al., 2014). In this article, the link between phosphorylated tau and mitochondrial dysfunction in AD is evaluated.
Tau Protein
Tau as a major microtubule-associated protein plays a significant role in neuronal processes. In adult human brains, high heterogeneity of the tau protein is apparent; there are six different tau isoforms, all of which are derived from a single gene by alternative mRNA splicing. The six isoforms of tau protein differ from each other in the number of microtubule-binding domains (3R/4R) (Lee et al., 1989) and in the presence or absence of either one or two projection domains (0N/1N/2N). Between the microtubule-binding domain and projection domain lies a basic proline-rich region (155–242), which contains abundant phosphorylation sites (Binder et al., 1985). The six isoforms appear to be broadly functionally similar, but each is likely to have precise, and to some extent distinctive, physiological roles. These isoforms appear to be differentially expressed during development. Normally, the 3R and 4R tau isoforms are expressed in a one-to-one ratio in most regions of adult brains (Ballatore et al., 2007).
The interaction of the proline-rich region of tau with the microtubule-surface contributes to microtubule stabilization (Amos, 2004). Phosphorylation as the most prominent post-translational modification of tau plays an important role in the dynamic equilibrium of tau with the microtubules (Arnold et al., 1996; Liu et al., 2004; Mazanetz and Fischer, 2007). It is well established that the serine/threonine-directed phosphorylation of tau directly regulates the binding affinity of tau for microtubules (Mazanetz and Fischer, 2007). The nonequilibrium of tau binding to the microtubules results in aggregation and fibrillization of tau and dysfunction of microtubules (Kuret et al., 2005). The microtubule network plays an essential role in axonal transport. It is likely that the resultant dysfunction of microtubules further leads to abnormal axonal transport and synaptic dysfunction. By modulating the microtubule network, tau has profound effects on axonal transport, which allows signaling molecules, trophic factors, and essential organelles including mitochondria and so on, to travel along the axons. Thus, tau contributes to vital structural and regulatory cellular functions.
Tau Impairs Mitochondrial Transport
To meet high energy demands and regulate calcium buffering of neuronal cells, efficient delivery of mitochondria in neurons is essential. The delivery of mitochondria is the task of microtubules, which perform a “rail track” function. Mitochondria are cargoes that are delivered by microtubule-associated proteins, including tau, across axon into synapses (Wang et al., 2015). Observations from studies of different cellular and mice models of AD show that overexpression and hyperphosphorylation of tau impair localization and distribution of mitochondria (Ebneth et al., 1998; Kopeikina et al., 2011; Shahpasand et al., 2012; Rodríguez-Martín et al., 2013), which further cause defects in axonal function and loss in synapses (Cabezas-Opazo et al., 2015; Wang et al., 2015).
The distribution of mitochondria in neurites containing tau aggregates was disrupted in an age-dependent manner in the rTg4510 mouse model (Kopeikina et al., 2011). Similar alteration of mitochondrial localization observed in human AD brains further confirmed the association of tau accumulation with mitochondrial translocation deficits (Kopeikina et al., 2011). Additionally, the reduction of soluble tau improved the aberrant mitochondrial trafficking in the rTg4510 mouse model (Kopeikina et al., 2011). In an axonal study of the squid AD model, it was filamentous rather than soluble forms of hyperphosphorylated tau that inhibited anterograde fast axonal transport through activating glycogen synthase kinase 3 (GSK3) and axonal protein phosphatase 1 (PP1) (Kanaan et al., 2011). Increased expression of glycogen synthase kinase-3β (GSK-3β) and the p25 activator of cyclin dependent kinase 5 were found to pause the mitochondrial movement in cortical neurons (Morel et al., 2010). At the same time, inhibition of GSK-3β reversed axonal transport disrupted by overexpression of tau in Drosophila (Mudher et al., 2004). These results show that mitochondrial transport is influenced by overexpression of tau, especially the aggregated tau. It is indicated that GSK-3β is involved in regulating overexpressed tau-induced mitochondrial translocation.
Abnormal phosphorylation of tau at AT8 sites (Ser199, Ser202, and Thr205) inhibited mitochondrial movement and affected mitochondrial distribution along the axons of cortical neurons in the mouse brain, which may contribute to the axonal degeneration (Shahpasand et al., 2012). As a possible underlying mechanism, it was reported that in K369I mutant tau transgenic K3 mice, phosphorylated tau trapped kinesin motor protein complex JIP1 in the soma. This aberrant JIP1 translocation caused cargo-selective (such as mitochondria) impairment of axonal transport (Ittner et al., 2009). Observation of pathological interaction of tau with JIP1 and trapping of JIP1 in the soma in AD patients further supports these findings in the mouse model (Ittner et al., 2009), while loss of axonal mitochondria enhances the abnormal phosphorylation and the toxicity of tau. Reduction of axonal mitochondria—caused by RNAi-mediated knockdown of Miro, an adaptor protein involved in axonal transport of mitochondria—led to abnormal tau phosphorylation at AD-related phosphorylation site Ser262 (Iijima-ando et al., 2012). These studies show a perishing interplay between abnormal phosphorylated tau and impaired mitochondrial distribution. A possible signaling pathway underneath the interplay is implicated. By trapping kinesin motor protein complex JIP1, hyperphosphorylated tau disrupts the transport of mitochondria into the axons and synapses. Loss of axonal mitochondria fails to maintain dynamic equilibrium of tau with the microtubules in the axons and enhances the abnormal phosphorylation of tau, which is further entangled in a vicious circle.
In a study with various neuronal and nonneuronal cell lines, it is shown that tau impaired not only axonal transport of organelles (including mitochondria), but also the transport of amyloid precursor protein (APP) (Mandelkow et al., 2003). Retarded APP transport caused by tau indicates a possible relationship between two vital pathogenic factors in AD. In primary neurons of a tau knockout mouse model, tau was required in the Aβ-induced impairment of axonal transport, and the inhibition of tau overexpression protected against the Aβ-induced defective axonal transport of mitochondria and neurotrophin receptor TrkA (Vossel et al., 2011). Evidence from these studies suggests a predominant role of tau in the mitochondrial transport impairment in AD.
Various pathological forms of tau, such as hyperphosphorylated and aggregated forms, have been indicated as noxious (Kopeikina et al., 2012). Current studies show that overexpression of hyperphosphorylated and aggregated forms of tau plays a vital role in the impairment of axonal transport, and also that the resultant aberrant localization and distribution of mitochondria further cause axonal damage and synapse degeneration.
Tau Impairs Mitochondrial Dynamics
Mitochondria are dynamic organelles that constantly undergo fission and fusion activities. Balanced mitochondrial fission and fusion are beneficial processes (Westermann, 2012). Firstly, mitochondrial fission/fusion dynamics promote mitochondrial distribution along axons into synapses (Chen et al., 2007). Secondly, they intermix metabolites and mitochondria to enable the establishment of mitochondrial networks, which are essential for transmitting mitochondrial membrane potential (Skulachev, 2001) and for buffering calcium signals (Szabadkai et al., 2006). Also, they can separate defective mitochondrial constituents to defend against reactive oxygen species (ROS) damage during aging (Westermann, 2008). In brief, balanced mitochondrial fission/fusion dynamics are essential to meet high energy demands and facilitate neuroprotective effects (Chen and Chan, 2009; Santos et al., 2010). A group of guanosine triphosphatases (GTPases) has been found to regulate mitochondrial fission and fusion processes. Dynamin-like protein 1 (DLP-1 or Drp1) and a small molecule fission protein-1(Fis1) are involved in the regulation of the fission process (Chan, 2006; Su et al., 2010b). The fusion process is regulated by mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optic atrophy protein 1 (OPA-1) (Cipolat et al., 2004; Youle and van der Bliek, 2012). Mitochondrial dynamics within the neuronal environment are mediated by the above-listed proteins. Mitochondrial morphology and function is tightly regulated in response to cellular and environmental stresses (Picard et al., 2013). It is reported that mitochondrial dysfunction and abnormal morphology are prominent features of AD (Wang et al., 2014b; Gao et al., 2017; Guo et al., 2017). It is generally accepted that the dynamic balance of mitochondrial fission and fusion is disturbed in AD, shifting toward immoderate fission (Wang et al., 2009; Bonda et al., 2010).
Abnormal interaction between hyperphosphorylated tau and Drp1 caused an excessive mitochondrial fission process and led to the degeneration of mitochondria and synapses in brain tissues of APP, APP/PS1, and 3xTg-AD mice. Similar results found in brain tissues from AD patients further improve the validity of the role of hyperphosphorylated tau in impaired mitochondrial dynamics (Manczak and Reddy, 2012a). In addition, reduction of Drp1 was able to protect against hyperphosphorylated tau-induced mitochondrial and synaptic impairment (Kandimalla et al., 2016). In a recent study about the effects of different forms of tau on mitochondrial dynamics, it is found that truncated tau fragmented mitochondria combined with reduced levels of OPA-1 (Pérez et al., 2017). In contrast, human wild-type full length tau (htau) impaired the balance of mitochondrial dynamics through increasing fusion proteins OPA-1, Mfn1, and Mfn2 and enhancing mitochondrial fusion activity in the HEK293 cell line and primary hippocampal neurons of rats (Li et al., 2016). Previous studies suggest that mitochondrial fusion is a protective process, while an excessive fission process is a sign of malfunction. Adverse results of these two studies may be due to the difference among the sensibility of diverse cell lines responding to the toxicity of tau. In Li et al.'s study, the htau promoted mitochondrial fusion and increased the cell viability at 48 h. After overexpression of htau, axonal degeneration and neurite loss were observed (Li et al., 2016). It is proposed that accumulated tau ameliorates acute apoptosis by promoting mitochondrial fusion at an early stage while it causes neuronal degeneration with increasing mitochondrial fission at later stage (Li et al., 2007; Wang et al., 2010, 2014a).
The dynamic balance of mitochondrial fission/fusion and normal mitochondrial distribution are essential for maintaining mitochondrial function (Chen and Chan, 2009). Evidence from these studies suggests that pathological forms of tau play a significant role in the impairment of mitochondrial fission/fusion dynamics in AD, mainly through a molecular mechanism of increasing mitochondrial fission protein such as Drp1 and decreasing fusion protein including OPA-1, Mfn1/2. Tau-induced abnormal mitochondrial dynamics and impaired mitochondrial distribution may further lead to mitochondrial dysfunction.
Tau Pathology and Mitochondrial Dysfunction in AD
Mitochondrial dysfunction plays a fundamental role in the pathogenesis of AD (Moreira et al., 2010). Defects in mitochondrial function are manifested by a variety of indicators, including decreased ATP synthesis, increased ROS production, impaired oxidative phosphorylation system (OXPHOS) complexes and antioxidant enzymes (Cabezas-Opazo et al., 2015). It is proposed that pathological forms of tau impair mitochondrial function. In both cell culture and transgenic mice studies, overexpression of tau inhibits mitochondrial function by decreasing the activity of complexes and antioxidant enzymes and repairing ATP synthesis and synaptic function (Eckert et al., 2011; Wang et al., 2015; Li et al., 2016). Perinuclear distribution of mitochondria causes ATP depletion, oxidative stress and even synaptic dysfunction (Chen and Zhong, 2014; Wang et al., 2014b). It is also found that N-terminal-truncated tau localized in mitochondrial membrane impaired ATP synthesis and membrane potential (Atlante et al., 2008). It is shown that overexpression and mislocalization of tau impair mitochondrial function mainly through decreasing ATP production and increasing oxidative stress, finally leading to synaptic dysfunction in AD.
Interestingly, indicators of mitochondrial dysfunction found in the AD patients are also evidenced in different AD-related mice models expressing pathological tau. Abnormal interaction of phosphorylated tau with voltage-dependent anion channel 1 protein (VDAC1) observed in AD patients was also found in APP, APP/PS1, and 3xTg-AD mice models (Manczak and Reddy, 2012b). It broke the balance of the opening and closure of mitochondrial pores and led to mitochondrial dysfunction (Manczak and Reddy, 2012b). The P301L tau transgenic mice presented notable mitochondrial dysfunction. Brains of these mice showed that mitochondrial complexes activities were significantly reduced, especially complex I and V. Moreover, impaired ATP synthesis together with decreased mitochondrial respiration and increased ROS levels were also noticed (David et al., 2005). In the triple transgenic AD mouse model that generated from cross-breeding of P301L tau transgenic pR5 mice and APPswePS2N141I double-transgenic APP152 mice, compromised mitochondrial function was notably observed (Rhein et al., 2009). Proteomic and functional studies found that expressions and activities of mitochondrial complex I and IV were significantly deregulated, and deregulation of complex I was remarkably tau-dependent. Additionally, these mice also exhibited evident lacking of ATP synthesis, increased ROS production and depolarized mitochondrial membrane potential (Rhein et al., 2009). In another triple transgenic AD mice (3xTg-AD) with transgenes APPswe, PS1M146V, and TauP301L, mitochondrial impairment was early evidenced by impaired mitochondrial respiration, and decreased pyruvate dehydrogenase (PDH), as well as increased oxidative stress (Yao et al., 2009).
Discussion
We have discussed here the effects of tau overexpression on mitochondrial transport, dynamics and function in the pathogenesis of AD. It is demonstrated that pathological forms of tau impair mitochondrial function through three aspects including mitochondrial transport, dynamics and bioenergetics. In spite of that, some AD mice models exhibited cognitive impairment before observation of NFTs. This evidence raises doubts about whether pathological tau is a trigger of the mitochondrial abnormalities that are one of the earliest features in AD. It is postulated that mitochondrial impairment may also modulate the pathological hallmark tau in AD (Mondragón-Rodríguez et al., 2013). However, the underlying mechanism between mitochondrial dysfunction and tau pathology in AD remains elusive.
Mitochondria are the main source of ROS, and mitochondrial oxidative damage is significantly associated with AD (Tönnies and Trushina, 2017). In a previous study, chronic oxidative stress in cultured neural cells induced by inhibition of glutathione synthesis, elevated phosphorylation of tau at AD-specific phospho-sites. It suggests that chronic oxidative stress is able to increase phosphorylation of tau (Su et al., 2010a). Treating cultured neuronal cells with ROS mimicking mitochondrial oxidative stress, promotes tau phosphorylation (Ibáñez-Salazar et al., 2017) by increasing the activity of GSK-3β (Lovell et al., 2004). In addition, astrocytes-mediated fatty acid oxidative products induced tau hyperphosphorylation in neurons; further co-treatment of these neurons with an antioxidant decreased levels of tau hyperphosphorylation. This study provides a direct link between oxidative stress and AD-relevant tauopathy (Patil and Chan, 2005). Treating mice lacking superoxide dismutase 2 (SOD2) with catalytic antioxidant could decrease the levels of AD-associated tau hyperphosphorylation, which indicates that mitochondrial oxidative stress contributes to abnormal hyperphosphorylation of tau (Melov et al., 2007). In addition, mitochondrial complex I inhibitor annonacin mediated redistribution of tau from the axons to the cell soma in cultured neurons (Escobar-Khondiker et al., 2007). In summary, accumulated mitochondrial dysfunction contributes to the progressive development of AD, possibly through a mechanism whereby mitochondrial oxidative stress promotes abnormal phosphorylation of tau. However, more studies are needed to find supportive evidence.
Mitochondria dysfunction, as a prominent early feature in the pathogenesis of AD, leads to phosphorylation and aggregation of tau. Meanwhile, pathological tau impairs the mitochondrial axonal transportation, mitochondrial dynamics and function. Accumulated mitochondrial impairment and tau pathology in a vicious circle affect neuronal and synaptic function, leading to memory loss and cognitive impairment in AD. The relationship between pathological tau and mitochondrial dysfunction in AD is like the story of the chicken and the egg. More evidence is needed to decide whether mitochondrial dysfunction is the cause or consequence of pathological tau. Moreover, further experiments focusing on the link between mitochondrial dysfunction and pathological tau may be helpful for developing therapeutic targets.
Author Contributions
FB has been responsible for providing ideas and polishing the manuscript. YC takes charge of searching for evidence and writing the manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors thank Jane Brooks and Elise Seldenrust, who are from University of St Andrews, for the help with editing the manuscript. This research was supported by the National Natural Science Foundation of China (No. 81671665), Jiangsu Provincial Key Medical Talents (No.ZDRCA2016085) and Natural Science Foundation of Jiangsu Province (No. BK20160071). None of the authors have a conflict of interest, financial or otherwise, directly or indirectly related to this work.
References
Amos, L. A. (2004). Microtubule structure and its stabilisation. Org. Biomol. Chem. 2, 2153–2160. doi: 10.1039/b403634d
Arnold, C. S., Johnson, G. V., Cole, R. N., Dong, D. L., Lee, M., and Hart, G. W. (1996). The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J. Biol. Chem. 271, 28741–28744. doi: 10.1074/jbc.271.46.28741
Atlante, A., Amadoro, G., Bobba, A., De Bari, L., Corsetti, V., Pappalardo, G., et al. (2008). A peptide containing residues 26–44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator. Biochim. Biophys. Acta 1777, 1289–1300. doi: 10.1016/j.bbabio.2008.07.004
Ballatore, C., Lee, V. M., and Trojanowski, J. Q. (2007). Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. 8, 663–672. doi: 10.1038/nrn2194
Binder, L. I., Frankfurter, A., and Rebhun, L. I. (1985). The distribution of tau in the mammalian central nervous system. J. Cell Biol. 101, 1371–1378. doi: 10.1083/jcb.101.4.1371
Bonda, D. J., Wang, X., Perry, G., Smith, M. A., and Zhu, X. (2010). Mitochondrial dynamics in Alzheimer's disease: opportunities for future treatment strategies. Drugs Aging 27, 181–192. doi: 10.2165/11532140-000000000-00000
Cabezas-Opazo, F. A., Vergara-Pulgar, K., Pérez, M. J., Jara, C., Osorio-Fuentealba, C., and Quintanilla, R. A. (2015). Mitochondrial dysfunction contributes to the pathogenesis of alzheimer's disease. Oxid. Med. Cell. Longev. 2015:509654. doi: 10.1155/2015/509654
Cai, Q., and Tammineni, P. (2017). Mitochondrial aspects of synaptic dysfunction in Alzheimer's disease. J. Alzheimer's Dis. 57, 1087–1103. doi: 10.3233/JAD-160726
Chan, D. C. (2006). Mitochondria: dynamic organelles in disease, aging, and development. Cell 125, 1241–1252. doi: 10.1016/j.cell.2006.06.010
Chen, H., and Chan, D. C. (2009). Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases. Hum. Mol. Genet. 18, 169–176. doi: 10.1093/hmg/ddp326
Chen, H., McCaffery, J. M., and Chan, D. C. (2007). Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130, 548–562. doi: 10.1016/j.cell.2007.06.026
Chen, Z., and Zhong, C. (2014). Oxidative stress in Alzheimer's disease. Neurosci. Bull. 30, 271–281. doi: 10.1007/s12264-013-1423-y
Cipolat, S., de Brito, O. M., Dal Zilio, B., and Scorrano, L. (2004). OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl. Acad. Sci. U.S.A. 101, 15927–15932. doi: 10.1073/pnas.0407043101
David, D. C., Hauptmann, S., Scherping, I., Schuessel, K., Keil, U., Rizzu, P., et al. (2005). Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J. Biol. Chem. 280, 23802–23814. doi: 10.1074/jbc.M500356200
Ebneth, A., Godemann, R., Stamer, K., Illenberger, S., Trinczek, B., Mandelkow, E.-M., et al. (1998). Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J. Cell Biol. 143, 777–794
Eckert, A., Nisbet, R., Grimm, A., and Götz, J. (2014). March separate, strike together - Role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease. Biochim. Biophys. Acta 1842, 1258–1266. doi: 10.1016/j.bbadis.2013.08.013
Eckert, A., Schmitt, K., and Götz, J. (2011). Mitochondrial dysfunction - the beginning of the end in Alzheimer ' s disease ? Separate and synergistic modes of tau and amyloid-β toxicity. Alzheimer's Res. Ther. 3:2011. doi: 10.1186/alzrt74
Escobar-Khondiker, M., Höllerhage, M., Muriel, M.-P., Champy, P., Bach, A., Depienne, C., et al. (2007). Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J. Neurosci. 27, 7827–7837. doi: 10.1523/JNEUROSCI.1644-07.2007
Gao, J., Wang, L., Liu, J., Xie, F., Su, B., and Wang, X. (2017). Abnormalities of mitochondrial dynamics in neurodegenerative diseases. Antioxidants 6, 25. doi: 10.3390/antiox6020025
Grundke-Iqbal, I., Iqbal, K., Tung, Y.-C., Quinlan, M., Wisniewski, H. M., and Binder, L. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913–4917. doi: 10.1073/pnas.83.13.4913
Guo, L., Tian, J., and Du, H. (2017). Mitochondrial dysfunction and synaptic transmission failure in Alzheimer's disease. J. Alzheimer's Dis. 57, 1071–1086. doi: 10.3233/JAD-160702
Hardy, J. A., and Higgins, G. A. (1992). Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185. doi: 10.1126/science.1566067
Hardy, J., and Selkoe, D. J. (2002). The amyloid hypothesis of alzheimer ' s disease: progress and problems on the road to therapeutics. Science 297, 353–356. doi: 10.1126/science.1072994
Ibáñez-Salazar, A., Bañuelos-Hernández, B., Rodríguez-Leyva, I., Chi-Ahumada, E., Monreal-Escalante, E., Jiménez-Capdeville, M. E., et al. (2017). Oxidative stress modifies the levels and phosphorylation state of tau protein in human fibroblasts. Front. Neurosci. 11:495. doi: 10.3389/fnins.2017.00495
Iijima-ando, K., Sekiya, M., Maruko-otake, A., Ohtake, Y., and Suzuki, E. (2012). Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease – related tau phosphorylation via PAR-1. PLoS Genet. 8:e1002918. doi: 10.1371/journal.pgen.1002918
Ittner, L. M., and Götz, J. (2011). Amyloid-β and tau - a toxic pas de deux in Alzheimer's disease. Nat. Rev. Neurosci. 12, 67–72. doi: 10.1038/nrn2967
Ittner, L. M., Ke, Y. D., and Götz, J. (2009). Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J. Biol. Chem. 284, 20909–20916. doi: 10.1074/jbc.M109.014472
Kanaan, N. M., Morfini, G. A., LaPointe, N. E., Pigino, G. F., Patterson, K. R., Song, Y., et al. (2011). Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J. Neurosci. 31, 9858–9868. doi: 10.1523/JNEUROSCI.0560-11.2011
Kandimalla, R., Manczak, M., Fry, D., Suneetha, Y., Sesaki, H., and Reddy, P. H. (2016). Reduced dynamin-related protein 1 protects against phosphorylated Tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease. Hum. Mol. Genet. 25, 4881–4897. doi: 10.1093/hmg/ddw312
Kopeikina, K., Hyman, B. T., and Spires-Jones, T. L. (2012). Soluble forms of tau are toxic in Alzheimer's disease. Transl. Neurosci. 3, 223–233. doi: 10.2478/s13380-012-0032-y
Kopeikina, K. J., Carlson, G. A., Pitstick, R., Ludvigson, A. E., Peters, A., Luebke, J. I., et al. (2011). Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain. Am. J. Pathol. 179, 2071–2082. doi: 10.1016/j.ajpath.2011.07.004
Kuret, J., Congdon, E. E., Li, G., Yin, H., Yu, X., and Zhong, Q. I. (2005). Evaluating triggers and enhancers of tau fibrillization. Microsc. R. Tech. 67, 141–155. doi: 10.1002/jemt.20187
Lee, G., Neve, R. L., and Kosik, K. S. (1989). The microtubule binding domain of tau protein. Neuron 2, 1615–1624. doi: 10.1016/0896-6273(89)90050-0
Li, H.-L., Wang, H.-H., Liu, S.-J., Deng, Y.-Q., Zhang, Y.-J., Tian, Q., et al. (2007). Phosphorylation of tau antagonizes apoptosis by stabilizing β-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 104, 3591–3596. doi: 10.1073/pnas.0609303104
Li, X. C., Hu, Y., Wang, Z. H., Luo, Y., Zhang, Y., Liu, X. P., et al. (2016). Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Sci. Rep. 6, 1–10. doi: 10.1038/srep24756
Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G. W., and Gong, C.-X. (2004). O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 101, 10804–10809. doi: 10.1073/pnas.0400348101
Lovell, M. A., Xiong, S., Xie, C., Davies, P., and Markesbery, W. R. (2004). Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. J. Alzheimer's Dis. 6, 659–671. doi: 10.3233/jad-2004-6610
Manczak, M., and Reddy, P. H. (2012a). Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: Implications for mitochondrial dysfunction and neuronal damage. Hum. Mol. Genet. 21, 2538–2547. doi: 10.1093/hmg/dds072
Manczak, M., and Reddy, P. H. (2012b). Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease. Hum. Mol. Genet. 21, 5131–5146. doi: 10.1093/hmg/dds360
Mandelkow, E. M., Stamer, K., Vogel, R., Thies, E., and Mandelkow, E. (2003). Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol. Aging 24, 1079–1085. doi: 10.1016/j.neurobiolaging.2003.04.007
Mazanetz, M. P., and Fischer, P. M. (2007). Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat. Rev. Drug Discov. 6, 464–479. doi: 10.1038/nrd2111
Melov, S., Adlard, P. A., Morten, K., Johnson, F., Golden, T. R., Hinerfeld, D., et al. (2007). Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS ONE 2:e536. doi: 10.1371/journal.pone.0000536
Mondragón-Rodríguez, S., Perry, G., Zhu, X., Moreira, P. I., Acevedo-Aquino, M. C., and Williams, S. (2013). Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: implications for Alzheimer's disease. Oxidative Med. Cell. Longevity 2013:940603. doi: 10.1155/2013/940603
Moreira, P. I., Carvalho, C., Zhu, X., Smith, M. A., and Perry, G. (2010). Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim. Biophys. Acta 1802, 2–10. doi: 10.1016/j.bbadis.2009.10.006
Morel, M., Authelet, M., Dedecker, R., and Brion, J. P. (2010). Glycogen synthase kinase-3β and the p25 activator of cyclin dependent kinase 5 increase pausing of mitochondria in neurons. Neuroscience 167, 1044–1056. doi: 10.1016/j.neuroscience.2010.02.077
Mudher, A., Shepherd, D., Newman, T. A., Mildren, P., Jukes, J. P., Squire, A., et al. (2004). GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol. Psychiatry 9, 522–530. doi: 10.1038/sj.mp.4001483
Nukina, N., and Ihara, Y. (1986). One of the antigenic determinants of paired helical filaments is related to tau protein. J. Biochem. 99, 1541–1544. doi: 10.1093/oxfordjournals.jbchem.a135625
Patil, S., and Chan, C. (2005). Palmitic and stearic fatty acids induce Alzheimer-like hyperphosphorylation of tau in primary rat cortical neurons. Neurosci. Lett. 384, 288–293. doi: 10.1016/j.neulet.2005.05.003
Pérez, M. J., Vergara-Pulgar, K., Jara, C., Cabezas-Opazo, F., and Quintanilla, R. A. (2017). Caspase-Cleaved Tau impairs mitochondrial dynamics in Alzheimer's Disease. Mol. Neurobiol. 55, 1–15. doi: 10.1007/s12035-017-0385-x
Picard, M., Shirihai, O. S., Gentil, B. J., and Burelle, Y. (2013). Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am. J. Physiol. 304, R393–R406. doi: 10.1152/ajpregu.00584.2012
Rhein, V., Song, X., Wiesner, A., Ittner, L. M., Baysang, G., Meier, F., et al. (2009). Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc. Nat. Acad. Sci. U.S.A. 106, 20057–20062. doi: 10.1073/pnas.0905529106
Rodríguez-Martín, T., Cuchillo-Ibáñez, I., Noble, W., Nyenya, F., Anderton, B. H., and Hanger, D. P. (2013). Tau phosphorylation affects its axonal transport and degradation. Neurobiol. Aging 34, 2146–2157. doi: 10.1016/j.neurobiolaging.2013.03.015
Santos, R. X., Correia, S. C., Wang, X., Perry, G., Smith, M. A., Moreira, P. I., et al. (2010). A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease. J. Alzheimer's Disease 20(Suppl.2), S401–S412. doi: 10.3233/JAD-2010-100666
Shahpasand, K., Uemura, I., Saito, T., Asano, T., Hata, K., Shibata, K., et al. (2012). Regulation of mitochondrial transport and inter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer's Disease. J. Neurosci. 32, 2430–2441. doi: 10.1523/JNEUROSCI.5927-11.2012
Skulachev, V. P. (2001). Mitochondrial filaments and clusters as intracellular power-transmitting cables. Trends Biochem. Sci. 26, 23–29. doi: 10.1016/S0968-0004(00)01735-7
Su, B., Wang, X., Lee, H., Tabaton, M., Perry, G., Smith, M. A., et al. (2010a). Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci. Lett. J. 468, 267–271. doi: 10.1016/j.neulet.2009.11.010
Su, B., Wang, X., Zheng, L., Perry, G., Smith, M. A., and Zhu, X. (2010b). Abnormal mitochondrial dynamics and Neurodegenerative diseases. Biochim. Biophys. Acta 1802, 135–142. doi: 10.1016/j.bbadis.2009.09.013
Szabadkai, G., Simoni, A. M., Bianchi, K., De Stefani, D., Leo, S., Wieckowski, M. R., et al. (2006). Mitochondrial dynamics and Ca2+ signaling. Biochim. Biophys. Acta 1763, 442–449. doi: 10.1016/j.bbamcr.2006.04.002
Tönnies, E., and Trushina, E. (2017). Oxidative stress, synaptic dysfunction, and Alzheimer's Disease. J. Alzheimer's Dis. 57, 1–17. doi: 10.3233/JAD-161088
Vossel, K. A, Zhang, K., Brodbeck, J., Daub, A. C., Sharma, P., Finkbeiner, S., et al. (2011). Tau reduction prevents Abeta-induced defects in axonal transport. Science 330, 10–13. doi: 10.1126/science.1194653.Tau
Wang, J.-Z., Wang, Z.-H., and Tian, Q. (2014a). Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer's disease. Neurosci. Bull. 30, 359–366. doi: 10.1007/s12264-013-1415-y
Wang, X., Su, B. O., Lee, H., Li, X., Perry, G., Smith, M. A., et al. (2009). Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J. Neurosci. 29, 9090–9103. doi: 10.1523/JNEUROSCI.1357-09.2009
Wang, X., Wang, W., Li, L., Perry, G., Lee, H., and Zhu, X. (2014b). Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochim. Biophys. Acta 1842, 1240–1247. doi: 10.1016/j.bbadis.2013.10.015
Wang, Z.-F., Yin, J., Zhang, Y., Zhu, L.-Q., Tian, Q., Wang, X.-C., et al. (2010). Overexpression of Tau proteins antagonizes Amyloid-β-Potentiated apoptosis through Mitochondria-Caspase-3 pathway in N2a cells. J. Alzheimer's Dis. 20, 145–157. doi: 10.3233/JAD-2010-1351
Wang, Z. X., Tan, L., and Yu, J. T. (2015). Axonal transport defects in Alzheimer's Disease. Mol. Neurobiol. 51, 1309–1321. doi: 10.1007/s12035-014-8810-x
Westermann, B. (2008). Molecular machinery of mitochondrial fusion and fission. J. Biol. Chem. 283, 13501–13505. doi: 10.1074/jbc.R800011200
Westermann, B. (2012). Bioenergetic role of mitochondrial fusion and fission. Biochim. Biophys. Acta 1817, 1833–1838. doi: 10.1016/j.bbabio.2012.02.033
Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., and Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc. Nat. Acad. Sci. U.S.A. 106, 14670–14675. doi: 10.1073/pnas.0903563106
Keywords: Alzheimer's disease, tau, mitochondrial transport, mitochondrial dynamics, mitochondrial dysfunction
Citation: Cheng Y and Bai F (2018) The Association of Tau With Mitochondrial Dysfunction in Alzheimer's Disease. Front. Neurosci. 12:163. doi: 10.3389/fnins.2018.00163
Received: 16 October 2017; Accepted: 28 February 2018;
Published: 22 March 2018.
Edited by:
Jesus Avila, Universidad Autonoma de Madrid, SpainReviewed by:
Cheng-Xin Gong, Institute for Basic Research in Developmental Disabilities (IBR), United StatesIsidre Ferrer, Universitat de Barcelona, Spain
Copyright © 2018 Cheng and Bai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Feng Bai, YmFpZmVuZzUxNUAxMjYuY29t