Abstract
Protein aggregation takes place in many neurodegenerative disorders. However, there is a controversy about the possible toxicity of these protein aggregates. In this review, this controversy is discussed, focussing on the tau aggregation that takes place in those disorders known as tauopathies.
INTRODUCTION
Many neurodegenerative disorders are characterized by their presence in neural tissue of aberrant protein aggregates (see Table 1). In general, these aggregates arise after the modification of a native protein. That modification could result in a conformational change of the native protein that promotes the aberrant aggregation.
Table 1.
Proteinopathies (aberrant aggregation) | |||
Disease | Protein | Pathological finding | Protein conformation |
Prion diseases | PrPSc | PrP amyloid plaques | β-sheet |
Alzheimer's disease | Aβ | Aβ amyloid plaques | β-sheet |
Tau | Paired helical filaments in neurofibrillary tangles | β-sheet + α-helix | |
Parkinson's disease | α-synuclein | Lewy bodies | β-sheet + α-helix |
Frontotemporal dementia | Tau | Straight filaments and paired helical filaments | ─ |
Pick's disease | Tau | Pick bodies | — |
Progressive supranuclear palsy | Tau | Straight filaments is neurfibrillary tangles | — |
Amyotrophic lateral sclerosis | Neurofilament | Neural aggregates | — |
Huntington's disease | Huntingtin | Nuclear inclusions | β-sheet |
Spinocerebellar ataxia | |||
Type 1 | Ataxin 1 | Nuclear inclusions | β-sheet |
Type 2 | Ataxin 2 | Cytoplasmic inclusions | β-sheet |
Machado-Joseph disease | Ataxin 3 | Nuclear inclusions | β-sheet |
The most studied model of this mechanism has been the prion protein where a change from an alpha helix to beta sheet structure facilitates the polymerization of a protein with a different conformation that appears to have a cytotoxic effect [1].
In a similar way, conformational changes between a native protein and its aberrant protein counterpart with capacity for self-assembly have been studied in many neurodegenerative diseases. Among the most common techniques used for these analyses are X-ray diffraction, nuclear magnetic resonance, circular dichroism, or Fourier-transformed infrared spectroscopy. Similarly, to the case of prion protein, in some disorders a change from alpha helix to beta sheet conformation has been suggested to cause protein aggregation (Table 1), probably because in alpha helix, intramolecular hydrogen bonds could occur whereas intramolecular hydrogen bonds are facilitated in beta sheet conformation, facilitating protein aggregation. However, there is one case, the formation of aberrant aggregates of tau, where the aggregated protein contains also a high proportion of alpha helix structure [2].
Although, in some cases, like that of prion protein, the formation of aberrant aggregates of protein could result in a toxic effect in the affected neurons [1], in other cases, like huntingtin aggregates, the formation of the aberrant aggregates could be a survival response of the affected neurons [3]. In other neurodegenerative diseases, it will be of interest to know if protein aggregation is synonymous of cell toxicity or not.
Protein conformation could also play a role in a possible toxic mechanism. In this way, a protein with a high proportion of alpha helix and hydrophobic regions could be inserted in cell membrane promoting toxic effects [4]. Additionally, the presence of aberrant polymers could affect the protein degradation cell machinery (the proteasome complex), decreasing its activity and promoting a toxic effect [5].
Recently, some good reviews have been published on protein aggregation and neurodegenerative disorders [6, 7]. In this review we will mainly focus on those aggregates assembled from tau protein, aggregates that could be present in the neurological disorders known as tauopathies (for a review see [8]) (Table 1).
TAU AGGREGATION
It has been described that large amounts of native or unmodified tau protein were enough to promote tau assembly into fibrillar polymers resembling those found in AD [9–12]. Thus, obviously, an increase in tau concentration will favour the formation of tau polymers. Recently, it has been reported that not all the brain areas have a similar amount of tau protein [13]. Thus, it suggests a different probability in the formation of tau polymers in different brain regions.
The amount of tau will be the consequence of its synthesis and its degradation. Changes in transcription have been indicated for other proteins related to neurodegenerative disorders [14], where a TATA binding protein may play a role. Tau degradation may take place through the proteasome complex [15, 16] and it has been suggested that such degradation could be regulated by posttranslational modifications occurring in tau molecule, like its phosphorylation [17]. Also, tau degradation by other proteases could be regulated by its level of phosphorylation [18]. It should be also indicated that in some cases like Parkinson's disease or Lafora disease, mutations in the E3 ubiquitin ligases like parkin [19] or malin [20] will result in the appearance of aberrant protein aggregates.
A conformational change, that could be followed by antibodies that react with tau molecule after that conformational change [21–24] has been also suggested to be required for the transition tau monomer-tau polymer.
Also, it has been suggested that different posttranslational modifications like phosphorylation [25], glycation [26], or truncation [27], may play a role in the formation of tau polymers.
Due to the alternative splicing of its heterogenous (or nuclear) RNA, different tau isoforms could be expressed and, therefore, different tau aggregates with different tau isoforms in different tauopathies could occur, but we will not discuss this point here. For further information see [8].
Mainly, studies on phosphorylation and truncation have been done. About truncation, it has been suggested that removal of the amino and/or carboxy terminal regions, leaving the tubulin binding region will facilitate tau polymerization [21, 22, 28].
Some work has been done in vitro [29] and in vivo [30, 31] about a possible role of tau phosphorylation on tau assembly, suggesting that in some conditions tau phosphorylation may increase the capacity of tau for its self-assembly. Not only an increase in serine/threonine phosphorylation of tau could regulate its aggregation but also an increase in tau tyrosine phosphorylation may increase the formation of tau aggregates [32]. This assembly process may involve the formation of oligomers [33], filaments, and aggregates of filaments (tangle-like structures). In the formation of these aggregates of filaments, glycation may play a role [26].
The possible relation between phosphorylation and tau aggregation has been studied in transgenic mice expressing human tau bearing some mutations found in human fronto-temporal dementia linked to chromosome 17 (FTDP-17) [31]. In this mouse, tau phosphorylation mainly occurs by GSK3 [34]. When a specific inhibitor of this kinase, lithium, was given to the transgenic mice no tau phosphorylation was found, and in addition no aggregation of the protein was detected [31] suggesting a correlation between tau phosphorylation and aggregation in this model. This result was supported by an additional experiment using another mouse also expressing human tau with a FTDP-17 mutation [30].
Alternatively, protein chaperones, acting on tau or in phosphotau, could modify the level of tau aggregation, examples could be the protein 14-3-3 [35], musashi-1 [36], or Pin-1 [37, 38]. The chaperone associated ubiquitin ligase CHIP could be able to target phosphotau for proteasomal degradation [16, 18].
TOXICITY OF PHOSPHOTAU
It has been described that tau binding to microtubules is regulated by the level of tau phosphorylation at some specific sites [39]. It is known that hyperphosphorylated tau binds with less affinity to microtubules resulting in the decrease in the interaction with microtubules, in a decrease of microtubule stability [8], and probably in a microtubule dysfunction inside the cell that could result in a toxic effect [40]. Also, tau phosphorylation could result, as indicated above, in a decrease of its proteolysis [17]. More recently, it has been indicated that expression of a tau mutant (P301L) could result in an increase of its phosphorylation, since once it is phosphorylated, that mutation can prevent the binding of those phosphatases involved in its dephosphorylation [41]. This phosphotau could have a decreased capacity for microtubule binding and it could be toxic for the cell. Additionally, it has been indicated that hyperphosphorylated tau can cause neurodegeneration, in the absence of large tau aggregates [42]. On the other hand, only the overexpression of wild-type human tau in a mouse is sufficient to cause tau phosphorylation, aggregation, and neural toxicity [43]. On the other hand, it has been suggested that tau phosphorylation may represent a protective function in AD [44].
TOXICITY OF AGGREGATED TAU
Sometime ago, the development of tau pathology, related with dementia in AD [45], was clearly described by Braak and Braak [46] by following the development of neurofibrillary lesions at different stages of the disease. Also, the formation of neurofibrillary (tau aggregates) pathology within those neurons of hippocampus and cerebral cortex affected at different stages was found. These neurons could degenerate yielding extracellular ghost tangles (eNFT) [47]. In the hippocampus, an inverse relation has been found between the number of eNFT and the number of surviving neurons [48–51]. It suggests that neurons that degenerate, have previously developed tau aggregates. On the other hand, it has been indicated that neurons bearing neurofibrillary lesions could survive for a long period of time [52], and, by comparing with other neurodegenerative disorders, like Huntington disease [3], it can be suggested that tau aggregates could protect against neurodegeneration by sequestering toxic (phospho?) monomeric tau that could be present in a high amount inside a cell in pathological conditions. Also, it has been suggested, using a transgenic mouse model [53], that behavioural (memory) deficits could be unrelated to the formation of tau polymers, although, more recently, the discussion of those experiments suggested that hyperphosphorylated, aggregated tau intermediates could be the ones that cause neurodegeneration [33]. In this way, the implication of different types of protein aggregates in neurodegeneration has been extensively discussed [19, 54]. A possibility about the existence of neurotoxic tau intermediate aggregates in human tauopathies is based in the fact that patients with FTDP-17 show an extensive neurodegeneration with a high level of tau phosphorylation but with a low number of tangles [55].
In any case, even if the formation of tau aggregates has a protective function for the neurons, that function is not working well, as described by Braak and Braak [46], and afterwards by Delacourte et al [56], indicating a correlation between progression of tau pathology and progression of the disease. This idea is supported by those experiments indicating that neural loss and neurofibrillary tangle number increase in parallel with the progression of the disease [57]. Similar results have been described in other neurological disorders like brain encelphalopathies, where the formation of aberrant polymers are related to the onset of neurodegeneration [1]; whereas this is far from clear in other disorders like Huntington disease.
References
- 1.Prusiner SB. Shattuck lecture—neurodegenerative diseases and prions. The New England Journal of Medicine. 2001;344(20):1516–1526. doi: 10.1056/NEJM200105173442006. [DOI] [PubMed] [Google Scholar]
- 2.Sadqi M, Hernández F, Pan U, et al. Alpha-helix structure in Alzheimer's disease aggregates of tau-protein. Biochemistry. 2002;41(22):7150–7155. doi: 10.1021/bi025777e. [DOI] [PubMed] [Google Scholar]
- 3.Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004;431(7010):805–810. doi: 10.1038/nature02998. [DOI] [PubMed] [Google Scholar]
- 4.Marchesi VT. An alternative interpretation of the amyloid Abeta hypothesis with regard to the pathogenesis of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(26):9093–9098. doi: 10.1073/pnas.0503181102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001;292(5521):1552–1555. doi: 10.1126/science.292.5521.1552. [DOI] [PubMed] [Google Scholar]
- 6.Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. The New England Journal of Medicine. 2003;349(6):583–596. doi: 10.1056/NEJMra023144. [DOI] [PubMed] [Google Scholar]
- 7.Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nature Medicine. 2004;10(suppl):S10–S17. doi: 10.1038/nm1066. [DOI] [PubMed] [Google Scholar]
- 8.Avila J, Lucas JJ, Pérez M, Hernández F . Role of tau protein in both physiological and pathological conditions. Physiological Reviews. 2004;84(2):361–384. doi: 10.1152/physrev.00024.2003. [DOI] [PubMed] [Google Scholar]
- 9.Crowther RA, Olesen OF, Jakes R, Goedert M. The microtubule binding repeats of tau protein assemble into filaments like those found in Alzheimer's disease. FEBS Letters. 1992;309(2):199–202. doi: 10.1016/0014-5793(92)81094-3. [DOI] [PubMed] [Google Scholar]
- 10.Montejo de Garcini E, Serrano L, Avila J. Self assembly of microtubule associated protein tau into filaments resembling those found in Alzheimer disease. Biochemical and Biophysical Research Communications. 1986;141(2):790–796. doi: 10.1016/s0006-291x(86)80242-x. [DOI] [PubMed] [Google Scholar]
- 11.Pérez M, Valpuesta JM, Medina M, Montejo de Garcini E, Avila J. Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. Journal of Neurochemistry. 1996;67(3):1183–1190. doi: 10.1046/j.1471-4159.1996.67031183.x. [DOI] [PubMed] [Google Scholar]
- 12.Wille H, Drewes G, Biernat J, Mandelkow EM, Mandelkow E. Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. The Journal of Cell Biology. 1992;118(3):573–584. doi: 10.1083/jcb.118.3.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Santa-María I, Hernández F, Smith MA, Perry G, Avila J, Moreno FJ. Neurotoxic dopamine quinone facilitates the assembly of tau into fibrillar polymers. Molecular and Cellular Biochemistry. 2005;278(1-2):203–212. doi: 10.1007/s11010-005-7499-6. [DOI] [PubMed] [Google Scholar]
- 14.van Roon-Mom WM, Reid SJ, Faull RL, Snell RG. TATA-binding protein in neurodegenerative disease. Neuroscience. 2005;133(4):863–872. doi: 10.1016/j.neuroscience.2005.03.024. [DOI] [PubMed] [Google Scholar]
- 15.David DC, Layfield R, Serpell L, Narain Y, Goedert M, Spillantini MG. Proteasomal degradation of tau protein. Journal of Neurochemistry. 2002;83(1):176–185. doi: 10.1046/j.1471-4159.2002.01137.x. [DOI] [PubMed] [Google Scholar]
- 16.Sahara N, Murayama M, Mizoroki T, et al. In vivo evidence of CHIP up-regulation attenuating tau aggregation. Journal of Neurochemistry. 2005;94(5):1254–1263. doi: 10.1111/j.1471-4159.2005.03272.x. [DOI] [PubMed] [Google Scholar]
- 17.Johnson GV, Jope RS, Binder LI. Proteolysis of tau by calpain. Biochemical and Biophysical Research Communications. 1989;163(3):1505–1511. doi: 10.1016/0006-291x(89)91150-9. [DOI] [PubMed] [Google Scholar]
- 18.Shimura H, Schwartz D, Gygi SP, Kosik KS. CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. The Journal of Biological Chemistry. 2004;279(6):4869–4876. doi: 10.1074/jbc.M305838200. [DOI] [PubMed] [Google Scholar]
- 19.Kahle PJ, Haass C. How does parkin ligate ubiquitin to Parkinson's disease? EMBO Reports. 2004;5(7):681–685. doi: 10.1038/sj.embor.7400188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Gentry MS, Worby CA, Dixon JE. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(24):8501–8506. doi: 10.1073/pnas.0503285102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Gamblin TC, Berry RW, Binder LI. Tau polymerization: role of the amino terminus. Biochemistry. 2003;42(7):2252–2257. doi: 10.1021/bi0272510. [DOI] [PubMed] [Google Scholar]
- 22.Gamblin TC, Berry RW, Binder LI. Modeling tau polymerization in vitro: a review and synthesis. Biochemistry. 2003;42(51):15009–15017. doi: 10.1021/bi035722s. [DOI] [PubMed] [Google Scholar]
- 23.Gamblin TC, King ME, Dawson H, et al. In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants. Biochemistry. 2000;39(20):6136–6144. doi: 10.1021/bi000201f. [DOI] [PubMed] [Google Scholar]
- 24.Gamblin TC, King ME, Kuret J, Berry RW, Binder LI. Oxidative regulation of fatty acid-induced tau polymerization. Biochemistry. 2000;39(46):14203–14210. doi: 10.1021/bi001876l. [DOI] [PubMed] [Google Scholar]
- 25.Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proceedings of the National Academy of Sciences of the United States of America. 1986;83(13):4913–4917. doi: 10.1073/pnas.83.13.4913. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Ledesma MD, Bonay P, Colaço C, Avila J. Analysis of microtubule-associated protein tau glycation in paired helical filaments. The Journal of Biological Chemistry. 1994;269(34):21614–21619. [PubMed] [Google Scholar]
- 27.Wischik CM, Lai RYK, Harrington CR. Modelling prion-like processing of tau protein in Alzheimer's disease for pharmaceutical development. In: Avila J, Brandt R, Kosik KS, editors. Brain Microtubule Associated Proteins: Modification in Disease. Chur, Switzerland: Harwood Academic; 1997. pp. 185–241. [Google Scholar]
- 28.Pérez M, Arrasate M, Montejo de Garcini E, Munoz V, Avila J. In vitro assembly of tau protein: mapping the regions involved in filament formation. Biochemistry. 2001;40(20):5983–5991. doi: 10.1021/bi002961w. [DOI] [PubMed] [Google Scholar]
- 29.Santa-María I, Hernández F, Martin CP, Avila J, Moreno FJ. Quinones facilitate the self-assembly of the phosphorylated tubulin binding region of tau into fibrillar polymers. Biochemistry. 2004;43(10):2888–2897. doi: 10.1021/bi035345j. [DOI] [PubMed] [Google Scholar]
- 30.Noble W, Planel E, Zehr C, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2005 ;102(19):6990–6995. doi: 10.1073/pnas.0500466102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Pérez M, Hernández F, Lim F, Diaz-Nido J, Avila J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. Journal of Alzheimer's Disease. 2003;5(4):301–308. doi: 10.3233/jad-2003-5405. [DOI] [PubMed] [Google Scholar]
- 32.Vega IE, Cui L, Propst JA, Hutton ML, Lee G, Yen SH. Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. Brain Research. Molecular Brain Research. 2005;138(2):135–144. doi: 10.1016/j.molbrainres.2005.04.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Duff K, Planel E. Untangling memory deficits. Nature Medicine. 2005;11(8):826–827. doi: 10.1038/nm0805-826. [DOI] [PubMed] [Google Scholar]
- 34.Lim F, Hernández F, Lucas JJ , Gomez-Ramos P, Moran MA, Avila J . FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Molecular and Cellular Neuroscience. 2001;18(6):702–714. doi: 10.1006/mcne.2001.1051. [DOI] [PubMed] [Google Scholar]
- 35.Hernández F, Cuadros R, Avila J. Zeta 14-3-3 protein favours the formation of human tau fibrillar polymers. Neuroscience Letters. 2004;357(2):143–146. doi: 10.1016/j.neulet.2003.12.049. [DOI] [PubMed] [Google Scholar]
- 36.Lovell MA, Markesbery WR. Ectopic expression of Musashi-1 in Alzheimer disease and Pick disease. Journal of Neuropathology and Experimental Neurology. 2005;64(8):675–680. doi: 10.1097/01.jnen.0000173891.17176.5b. [DOI] [PubMed] [Google Scholar]
- 37.Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature. 1999;399(6738):784–788. doi: 10.1038/21650. [DOI] [PubMed] [Google Scholar]
- 38.Poli M, Gatta LB, Dominici R, et al. DNA sequence variations in the prolyl isomerase Pin1 gene and Alzheimer's disease. Neuroscience Letters. 2005;389(2):66–70. doi: 10.1016/j.neulet.2005.07.027. [DOI] [PubMed] [Google Scholar]
- 39.Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annual Review of Neuroscience. 2001;24:1121–1159. doi: 10.1146/annurev.neuro.24.1.1121. [DOI] [PubMed] [Google Scholar]
- 40.Feinstein SC, Wilson L. Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death. Biochimica et Biophysica Acta. 2005;1739(2-3):268–279. doi: 10.1016/j.bbadis.2004.07.002. [DOI] [PubMed] [Google Scholar]
- 41.Goedert M, Satumtira S, Jakes R, et al. Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations. Journal of Neurochemistry. 2000;75(5):2155–2162. doi: 10.1046/j.1471-4159.2000.0752155.x. [DOI] [PubMed] [Google Scholar]
- 42.Brandt R, Hundelt M, Shahani N. Tau alteration and neuronal degeneration in tauopathies: mechanisms and models. Biochimica et Biophysica Acta. 2005;1739(2-3):331–354. doi: 10.1016/j.bbadis.2004.06.018. [DOI] [PubMed] [Google Scholar]
- 43.Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. The Journal of Neuroscience. 2005;25(22):5446–5454. doi: 10.1523/JNEUROSCI.4637-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Lee HG, Perry G, Moreira PI, et al. Tau phosphorylation in Alzheimer's disease: pathogen or protector? Trends in Molecular Medicine. 2005;11(4):164–169. doi: 10.1016/j.molmed.2005.02.008. [DOI] [PubMed] [Google Scholar]
- 45.Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992;42(3 pt 1):631–639. doi: 10.1212/wnl.42.3.631. [DOI] [PubMed] [Google Scholar]
- 46.Braak H, Braak E. Neuropathological stageing of Alzheimerrelated changes. Acta Neuropathologica (Berl) 1991;82(4):239–259. doi: 10.1007/BF00308809. [DOI] [PubMed] [Google Scholar]
- 47.Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die gesamte Neurologie und Psychiatrie. 1911;4:356–385. [Google Scholar]
- 48.Cras P, Smith MA, Richey PL, Siedlak SL, Mulvihill P, Perry G. Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease. Acta Neuropathologica (Berl) 1995;89(4):291–295. doi: 10.1007/BF00309621. [DOI] [PubMed] [Google Scholar]
- 49.Fukutani Y, Kobayashi K, Nakamura I, Watanabe K, Isaki K, Cairns NJ. Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease. Neuroscience Letters. 1995;200(1):57–60. doi: 10.1016/0304-3940(95)12083-g. [DOI] [PubMed] [Google Scholar]
- 50.Bondareff W, Mountjoy CQ, Roth M, Hauser DL. Neurofibrillary degeneration and neuronal loss in Alzheimer's disease. Neurobiology of Aging. 1989;10(6):709–715. doi: 10.1016/0197-4580(89)90007-9. [DOI] [PubMed] [Google Scholar]
- 51.Goedert M. Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 1999;354(1386):1101–1118. doi: 10.1098/rstb.1999.0466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. Journal of Neuropathology and Experimental Neurology. 1999;58(2):188–197. doi: 10.1097/00005072-199902000-00008. [DOI] [PubMed] [Google Scholar]
- 53.Santacruz K, Lewis J, Spires T, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005;309(5733):476–481. doi: 10.1126/science.1113694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annual Review of Neuroscience. 2003;26:267–298. doi: 10.1146/annurev.neuro.26.010302.081142. [DOI] [PubMed] [Google Scholar]
- 55.Bird TD, Nochlin D, Poorkaj P, et al. A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L) Brain. 1999;122(pt 4):741–756. doi: 10.1093/brain/122.4.741. [DOI] [PubMed] [Google Scholar]
- 56.Delacourte A, David JP, Sergeant N, et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology. 1999;52(6):1158–1165. doi: 10.1212/wnl.52.6.1158. [DOI] [PubMed] [Google Scholar]
- 57.Gomez-Isla T, Hollister R, West H, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Annals of Neurology. 1997;41(1):17–24. doi: 10.1002/ana.410410106. [DOI] [PubMed] [Google Scholar]