Tau Proteins

Tau Hyperphosphorylation Causes or Enhances NFT Formation

Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice

Feng Bian^1,*,

Rathna Nath¹,

Gregg Sobocinski²,

Robert N. Booher³,

William J. Lipinski¹,

Michael J. Callahan¹,

Amy Pack¹,

Kevin K.-W. Wang¹,

Lary C. Walker¹

Keywords:

Alzheimer;

axon;

cdk5;

electron microscopy;

kinase;

tau;

transgenic;

phosphorylation;

p35;

neurofibrillary tangle;

platelet-derived growth factor

Abstract

Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles. J. Comp. Neurol. 446:257–266, 2002. © 2002 Wiley-Liss, Inc.

View Full Article (HTML) Get PDF (2688K

Minireview

Tau Phosphorylation, Tangles, and Neurodegeneration: The Chicken or the Egg?

Daniel H Geschwind^,^a^,

^aNeurogenetics Program, Neurology Department, Center for Neurobehavioral Genetics, The Neuropsychiatric Institute, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095 USA

Available online 27 November 2003.

Abstract

Pathological aggregation of the microtubule-associated protein tau is a common feature of many neurodegenerative diseases. Although tau aggregation is associated with abnormal tau phosphorylation, the role of phosphorylation in the initiation of neurodegeneration has been unclear. Now, several animal models and data from human patients provide converging evidence that aberrant tau phosphorylation can cause a neurodegenerative phenotype similar to that seen in human neurodegenerative diseases.

Article Outline

Main Text

Introduction

Tau, Amyloid, and Regional Vulnerability

Main Text

Introduction

Pathologic deposition of the microtubule (MT)-associated protein tau, in the form of hyperphosphorylated inclusions or filamentous neurofibrillary tangles (NFTs), is one of the defining features of adult-onset neurodegenerative diseases such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (reviewed in [Lee et al. 2001] and [Buee et al. 2000]). Until recently, much of the genetic evidence for AD pointed to the generation of amyloid-forming Aβ peptides. Hyperphosphorylated insoluble tau in the form of NFTs was considered by many to be a relative bystander, despite the persistent association of tau deposition with dysfunctional neurons within diseased brains and cognitive dysfunction in normal aging (e.g., [Braak and Braak 1996] and[Green et al. 2000]).

The identification of highly penetrant, dominantly inherited mutations in tau causing the related dementia, FTDP-17, demonstrated conclusively that disruption of tau homeostasis could be a primary cause of neurodegeneration (Poorkaj et al. 1998) and (Hutton et al. 1998). FTDP-17 is a clinically and pathologically heterogeneous group of disorders that includes Pick's disease (Lee et al. 2001) and (Bird et al. 2003). A key feature of these conditions is an absence of significant amyloid pathology. However, while tau deposition in the form of NFTs is a defining feature of AD, no mutations in tau have been identified in AD or sporadic cases of FTD, and tau mutations account for only about 15% of inherited FTD cases (Bird et al. 2003) and (Lee et al. 2001). Therefore, understanding the factors that lead to the formation of pathological aggregates in the context of nonmutant tau in AD, FTD, and related neurodegenerative disorders is of major importance. Additionally, in AD, where both insoluble amyloid and tau deposition are present, the temporal or causal relationship between the cascade of amyloid deposition or tau aggregation and the relationship of both of these processes to cell death and dysfunction remain as gaping holes in our understanding.

NFTs seen in patients' brains are intracellular deposits composed of insoluble, hyperphosphorylated tau in a filamentous form, classically the paired helical (PHF), ribbon-like, or straight filament. Normally, tau is distributed extensively and MT associated in axons, but when hyperphosphorylated in its pretangle form, its affinity for MTs is significantly reduced and it becomes preferentially located in the somatodendritic compartment. Tau self-aggregates in vitro in a concentration-dependent manner, forming both straight and paired helical filaments identical to those observed in vivo. This process of tau polymerization is accelerated by a number of factors including polyanionic compounds such as glycosaminoglycans and nucleic acids, certain fatty acids, and hyperphosphorylation (Lee et al. 2001) and (Buee et al. 2000).

Tau phosporylation plays a normal physiologic role in decreasing tau's affinity for MTs and is an important regulator of MT polymerization during development. Tau has approximately 20 to 30 potential phosphorylation sites, many of which are putative targets of proline-directed serine/threonine kinases. Accumulating evidence suggests that two such kinases, glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase-5 (cdk5), are major tau kinases in vitro and in vivo. In AD, FTD, and PSP, insoluble PHF tau and its other pathologically aggregated forms invariably contain tau hyperphosphorylated on residues that overlap with GSK-3β and cdk5 targets. However, until recently it has been unclear whether aberrant tau phosphorylation by these or other kinases, such as p42/44 MAP Kinase (MAPK) and p38 MAPK (Buee et al. 2000) and (Lee et al. 2001), can cause NFT formation in vivo.

Tau Hyperphosphorylation Causes or Enhances NFT Formation

Evidence from the fly (Wittmann et al. 2001) and (Jackson et al. 2002) and the mouse (Cruz et al., 2003 [this issue of Neuron]) suggests that insoluble aggregates such as NFTs and amyloid plaques are signposts of damage already done; tau-related neurodegeneration can occur without, or precede, frank NFT formation. However, processes that accelerate NFT formation inevitably worsen neurodegeneration, supporting the concept that NFTs mark a critical, albeit probably later, process in disease progression. Previous work has shown that tau hyperphosphorylation by GSK-3β in the fly (Jackson et al., 2002) and cdk5 in mouse (Noble et al., 2003) can cause or accelerate NFT formation in vivo, with an attendant worsening of neurodegeneration. However, these effects were observed on a background of either wt tau overexpression or expression of a mutant tau transgene, raising the question of whether significant tau hyperphosphorylation alone under normal conditions may lead to neurofibrillary tau pathology. If so, perhaps tau kinases become an even more attractive target for therapeutic development. Two previous studies of cdk5 dysregulation have shown pathologic tau phosphorylation at the pretangle stage and evidence of disruption of the axonal cytoskeleton. But, while previous studies of p35-25-induced cdk5 overactivity had demonstrated that p25-induced cdk5 activation caused neurodegeneration in vitro (Patrick et al., 1999), no evidence of NFTs or neurodegeneration was identified in these two mouse models of p25/cdk5 overexpression(Ahlijanian et al. 2000) and (Bian et al. 2002).

In this issue of Neuron, Cruz et al. (2003) again examine whether cdk5 activation can cause neurofibrillary pathology and neurodegeneration by overexpressing the cdk5 activator, p25, in the postnatal mouse forebrain under control of an inducible CamK-II promoter, resulting in an approximately 2-fold induction in cdk5 activity and increased specificity for pathological substrates, such as tau and APP. Between 5 and 12 weeks after cdk5 induction, a time-dependent decrease in brain weight, as well as prominent neuronal loss in the cerebral cortex, along with astrogliosis and caspase 3 activation, was observed. Although there was no overt change in tau protein expression itself, insoluble pathologic tau with epitopes and conformation similar to that found in human AD brains was observed to accumulate in the mice overexpressing p25, demonstrated by a combination of immunoblotting, mass spectroscopy, and electron microscopy. Despite the clear biochemical and immunocytochemical evidence of tau hyperphosphorylation followed by its subsequent insolubility and aggregation, no clear neurofibrillary pathology as evidenced by light microscopy, thioflavin-S, or silver staining was seen at 12 to 16 weeks. However, by 27 weeks of cdk5 induction, neurofibrillary-like pathology was abundantly visible on light and electron microscopy in the cerebral cortex and hippocampus. The ultrastructural characteristics of these NFTs and their periodicity have not been characterized, so whether they are orthologous to straight filaments or PHF observed in human FTD or AD is unknown. The interpretation of filament ultrastructure is also complicated by differences in tau isoforms between mice and humans, which could lead to different filament morphologies. However, the phosphorylation pattern, insolubility, and light microscopic appearance described by Cruz et al. are consistent with these deposits being typical NFTs, and their distribution correlates with the regional pattern of cdk5 activation. In the future, it will be important to determine filament ultrastructure and the relationship between behavioral abnormalities and the timing and topology of neuronal loss and NFT appearance.

Why this model of cdk5 activation produces striking neurodegeneration and NFT formation, and previous models did not, is not known. Cruz et al. suggest that NFT formation is most likely due to the significantly greater cdk5 activation present in this model relative to previous models. The differences in promoters used in each of these models may also be contributory. In any regard, Cruz et al. provide the strongest evidence to date that aberrant tau kinase activity of any kind can lead to neurodegeneration and tau neurofibrillary pathology in vivo in the absence of tau dysregulation or mutations. These findings add to a growing body of evidence that NFTs or NFT-like pathology can be caused and/or accelerated by tau kinase overactivity in vivo (e.g., [Jackson et al. 2002], [Noble et al. 2003] and [Liou et al. 2003]) and firmly establishes tau phosphorylation as a potential therapeutic target in AD and FTD.

Recently, Noble et al. (2003) demonstrated that p25/cdk5 overactivation, in conjunction with expression of human tau containing the most common FTD-causing mutation in mouse, is associated with concomitant GSK-3α/β activation. Thus, although p25/cdk5 activation provides the initial insult in the Noble et al. model, GSK-3β is likely to be playing a role. Why GSK-3β activation is not observed in the model developed by Cruz et al. is not known—it may not be relevant in the context of such high cdk5 activity. The authors propose that GSK-3β may act to produce NFTs in the context of mutant or overexpressed tau, rather than normal tau. However, the persistent localization of GSK-3β with pretangle and tangle-bearing neurons in human AD suggests otherwise.

Although the circumstantial evidence is strong, it is not yet certain whether the neurodegeneration in the Cruz et al. model of p25 overexpression is a direct consequence of tau hyperphosphorylation by cdk5 or occurs via another signaling cascade. Cdk5 has many substrates, including proteins associated with neurodegeneration, such as APP (which are preferentially hyperphosphorylated by the p25/cdk5 complex; [Cruz et al. 2003] and [Dhavan and Tsai 2001]). Cdk5 is also involved in several aspects of neuronal differentiation as a link between extracellular signals and the cytoskeleton and thus could lead to cell dysfunction and death via a number of different pathways. Additionally, Cruz et al. demonstrate that tau is hyperphosphorylated on sites that are not known cdk5 targets and that two other known tau kinases may be activated, suggesting that at least some of the effects of p25 overactivation are indirect. Whether this indirect effect occurs through activation of other kinases, by downregulation of phosphatases, or somehow by altering the affinity of peptidyl-prolyl isomerases for tau (favoring a conformation not permissive for tau dephosphorylation) are important issues that now need to be addressed. Nevertheless, it is becoming clear that direct or indirect tau hyperphosphorylation via at least two proline-directed kinases can accelerate or cause neurodegeneration and NFT formation.

The importance of dephosphorylation in tauopathy is highlighted by the ability of the phosphorylation-dependent prolyl isomerase, Pin1, to provide relative protection from age-dependent neurodegeneration (Liou et al., 2003). Pin1 recognizes specific phosphorylated serine or threonine residues in tau that are followed by proline residues and catalyzes a critical conformational change that allows dephosphorylation at these residues to occur. Pin1 expression is inversely correlated with markers of neurofibrillary pathology in human AD brains, and Pin^−/−mice develop tau hyperphosphorylation, NFTs, and age-dependent neurodegeneration (Liou et al., 2003). This pathology is very similar to that caused by misexpression of either mutant or wt tau in other models (e.g., [Lewis et al. 2001], [Allen et al. 2002] and [Andorfer et al. 2003]), emphasizing that multiple pathways affecting tau expression levels, dephosphorylation (e.g., Kins et al., 2001), and phosphorylation may coalesce in a common phenotype characterized by tau hyperphosphorylation, aggregation, and NFT formation. Current evidence shows that the known FTDP-17-causing tau mutations either disrupt MT binding or affect tau splicing, leading to tau isoform imbalance (Lee et al. 2001) and (Hutton et al. 1998). Therefore, one feature potentially in common with the human mutations and animal models of tauopathy is an increase in free tau unbound to microtubules. Since tau polymerization into filaments is concentration dependent in vitro, this provides an obvious common mechanism for tau aggregation and NFT formation in vivo(Figure 1).

Full-size image (40K) - Opens new window

Full-size image (40K)
High-quality image (186K)

Figure 1. Tau Aggregation and Neurodegeneration: The Balance of Tau Phosphorylation

Tau is tightly balanced between being MT bound or free, depending on the state of the cell. Factors that promote an increase in unbound tau and aggregation are highlighted with red arrows (e.g., tau kinases), and protective factors are blue (e.g., tau phosphatases). This model focuses on a toxic gain-of-function mechanism based on increased tau aggregation and depicts cdk5 as acting upstream of GSK-3β. Loss of function, such as cytoskeletal disruption based on tau hyperphosphorylation and MT dysregulation, may contribute as well. Genetic and environmental factors may act at many steps. For example, tau mutations lead to increased free tau or tau isoforms that may be more prone to aggregate, whereas ApoE may act on Aβ42 and Tau. For many of the tauopathies, such as FTD, this process occurs independently of Aβ42.

This of course begs several questions: is there a common mechanism that leads to neurodegeneration in these different models of tauopathy, whether the model is based on tau misexpression, mutation, or altered kinase activity? The pervasive association of tau insolubility, the common pattern of pathological tau phosphorylation, and the histological signs of tau deposition observed in these models suggest that this is the case, but it is not certain. Perhaps, most relevant to the current discussion, are cdk5, GSK-3β, and other tau kinases acting in series or in parallel? The recent paper by Noble et al. (2003) and in vitro evidence suggest that cdk5 could be upstream of GSK-3β, serving to prime tau at key epitopes that modulate tau's affinity for microtubules. This hypothesis can be tested in vivo, since the detrimental effects of GSK-3β should be attenuated on a background of conditional cdk5 inactivation. Furthermore, specific kinase inhibitors can be tested to assess their ability to modulate the pathology observed in animals with mutant tau transgenes to test the primacy of particular kinase or phosphatase pathways. Of course, all of these mechanisms being studied in animal models need to be considered from the perspective of their potential overlap with the pathological alterations observed in human subjects (e.g., [Patrick et al. 1999] and [Liou et al. 2003]).

Tau, Amyloid, and Regional Vulnerability

Finally, it is necessary to consider tau phosphorylation in the context of two issues that seem central to our understanding and treatment of these neurodegenerative diseases. (1) How might these pathways involving tau intersect with the amyloid cascade that is proposed to lead to neurodegeneration in AD? (2) Do any of these processes or mechanisms explain the regional vulnerability that is the hallmark of human neurodegenerative diseases, such as FTD and AD? With regard to the first question, current evidence supports that view that Aβ could lie upstream of tau in AD, since increased Aβ42 leads to increased neurodegeneration and NFTs in mouse models carrying FTDP-17 causing tau mutations. We have previously speculated that GSK-3β could potentially mediate this toxic effect of amyloid (Jackson et al., 2002). Fibrillar Aβ42 fragments induce GSK-3β activation in vitro, leading to tau phosphorylation and apoptosis. Other kinases such as p38 MAPK, p42/44 MAPK, and CDK5 may play similar roles (Lee et al. 2000) and(Zheng et al. 2002). This cascade of kinase induction by Aβ42 could be a particularly vicious circle, as at least one form of GSK3 is involved in Aβ42 production (Phiel et al., 2003). In the case of sporadic disease, it is also equally plausible that genetic and environmental factors that increase amyloid deposition, such as ApoE isoforms, oxidative stress, etc., also induce tau aggregation or hyperphosphorylation, and the two aggregation pathways are initiated concurrently for AD, or alone, as would be the case in FTD.

One of the most constant features of AD and FTD are their distinct clinical presentations, which reflect the distinct early regional pathology in these disorders. We have speculated that this regional vulnerability in FTD may have a developmental component that alters neuronal patterning or phenotype generation in a manner that would render that region more susceptible to the later insults of aging (Geschwind and Miller, 2001). Genes with a dual role in patterning and neurodegeneration could contribute to the focal nature of these disorders, and both cdk5 and GSK3 have important roles in CNS patterning and development outside of their role as tau kinases (Anderton et al., 2000).

Recent evidence indicates that the regulation of tau phosphorylation is another potential source of regional susceptibility. For example, cdk5 overactivation under the control of the NSE promoter shifts the distribution of pathology in transgenic mice overexpressing the P301L mutation to cortical, in addition to more subcortical regions (Noble et al., 2003). The interpretation of regional vulnerability in animal models is confounded by the effect of different promoters, genetic background, and transgene insertion position. Although the use of a relatively ubiquitous neuronal promoter lessens these concerns, it is still important to consider the human data when assessing regional vulnerability. In human AD, the distribution of both GSK-3β and cdk5 are associated with pretangle or tangle-bearing neurons, suggesting that both neurons could be involved in early vulnerability (Patrick et al. 1999), (Pei et al. 1999) and (Yamaguchi et al. 1996). In this regard, it is also notable that Pin1 expression is highest in human neuronal populations that are less vulnerable to AD, consistent with its neuroprotective function (Liou et al., 2003). However, the more superficial layers of cortex where Pin1 was reported to be the most abundant contain the most vulnerable populations in FTD. This emphasizes that the individual factors leading to regional vulnerability in one dementia may not be acting in another, since the primary regions affected are so distinct. In any event, the concept of regional vulnerability represents something of a paradox, since the known disease-causing mutations all affect proteins that are widely expressed. Resolving this paradox, and therefore understanding the mechanisms underlying this focal susceptibility, is central to understanding these neurodegenerative diseases.

Acknowledgements

The author thanks his collaborators and coworkers, especially George Jackson, M.D., Ph.D., and Martina Wiedau-Pazos, M.D., Ph.D., for stimulating discussions and Bonita Porch for editorial assistance. Because of space limitations, the author apologizes for not being able to cite all who have made significant contributions to this growing body of knowledge.

References

Ahlijanian et al. 2000 M.K Ahlijanian, N.X Barrezueta, R.D Williams, A Jakowski, K.P Kowsz, S McCarthy, T Coskran, A Carlo, P.A Seymour and J.E Burkhardt et al., Proc. Natl. Acad. Sci. USA 97(2000), pp. 2910–2915. View Record in Scopus | Cited By in Scopus (201)

Allen et al. 2002 B Allen, E Ingram, M Takao, M.J Smith, R Jakes, K Virdee, H Yoshida, M Holzer, M Craxton and P.C Emson et al., J. Neurosci. 22 (2002), pp. 9340–9351. View Record in Scopus |Cited By in Scopus (175)

Anderton et al. 2000 B.H Anderton, R Dayanandan, R Killick and S Lovestone, Mol. Med. Today 6(2000), pp. 54–59. Abstract | Article |

PDF (102 K) | View Record in Scopus | Cited By in Scopus (39)

Andorfer et al. 2003 C Andorfer, Y Kress, M Espinoza, R de Silva, K.L Tucker, Y.A Barde, K Duff and P Davies, J. Neurochem. 86 (2003), pp. 582–590. View Record in Scopus | Cited By in Scopus (150)

Bian et al. 2002 F Bian, R Nath, G Sobocinski, R.N Booher, W.J Lipinski, M.J Callahan, A Pack, K.K Wang and L.C Walker, J. Comp. Neurol. 446 (2002), pp. 257–266. View Record in Scopus |Cited By in Scopus (66)

Bird et al. 2003 T Bird, D Knopman, J VanSwieten, S Rosso, H Feldman, H Tanabe, N Graff-Raford, D Geschwind, P Verpillat and M Hutton, Ann. Neurol. 54 (Suppl 5) (2003), pp. S29–S31.View Record in Scopus | Cited By in Scopus (44)

Braak and Braak 1996 H Braak and E Braak, Acta Neurol, Scand. Suppl. 165 (1996), pp. 3–12.View Record in Scopus | Cited By in Scopus (243)

Buee et al. 2000 L Buee, T Bussiere, V Buee-Scherrer, A Delacourte and P.R Hof, Brain Res. Rev. 33 (2000), pp. 95–130. Abstract | Article |

PDF (2399 K) | View Record in Scopus | Cited By in Scopus (621)

Cruz et al. 2003 J.C Cruz, H.-C Tseng, J.A Goldman, H Shih and L.-H Tsai, Neuron 40 (2003), pp. 471–483 , this issue. Article |

PDF (711 K) | View Record in Scopus | Cited By in Scopus (204)

Dhavan and Tsai 2001 R Dhavan and L.H Tsai, Nat. Rev. Mol. Cell Biol. 2 (2001), pp. 749–759.View Record in Scopus | Cited By in Scopus (459)

Geschwind and Miller 2001 D.H Geschwind and B.L Miller, Am. J. Med. Genet. 101 (2001), pp. 370–381. View Record in Scopus | Cited By in Scopus (50)

Green et al. 2000 M.S Green, J.A Kaye and M.J Ball, Neurology 54 (2000), pp. 105–113. View Record in Scopus | Cited By in Scopus (63)

Hutton et al. 1998 M Hutton, C.L Lendon, P Rizzu, M Baker, S Froelich, H Houlden, S Pickering-Brown, S Chakraverty, A Isaacs and A Grover et al., Nature 393 (1998), pp. 702–705.

Jackson et al. 2002 G.R Jackson, M Wiedau-Pazos, T.K Sang, N Wagle, C.A Brown, S Massachi and D.H Geschwind, Neuron 34 (2002), pp. 509–519. Article |

PDF (581 K) | View Record in Scopus | Cited By in Scopus (232)

Kins et al. 2001 S Kins, A Crameri, D.R Evans, B.A Hemmings, R.M Nitsch and J Gotz, J. Biol. Chem. 276 (2001), pp. 38193–38200. View Record in Scopus | Cited By in Scopus (101)

Lee et al. 2000 M.S Lee, Y.T Kwon, M Li, J Peng, R.M Friedlander and L.H Tsai, Nature 405(2000), pp. 360–364. View Record in Scopus | Cited By in Scopus (547)

Lee et al. 2001 V.M Lee, M Goedert and J.Q Trojanowski, Annu. Rev. Neurosci. 24 (2001), pp. 1121–1159. View Record in Scopus | Cited By in Scopus (898)

Lewis et al. 2001 J Lewis, D.W Dickson, W.L Lin, L Chisholm, A Corral, G Jones, S.H Yen, N Sahara, L Skipper and D Yager et al., Science 293 (2001), pp. 1487–1491. View Record in Scopus | Cited By in Scopus (619)

Liou et al. 2003 Y.C Liou, A Sun, A Ryo, X.Z Zhou, Z.X Yu, H.K Huang, T Uchida, R Bronson, G Bing and X Li et al., Nature 424 (2003), pp. 556–561. View Record in Scopus | Cited By in Scopus (152)

Noble et al. 2003 W Noble, V Olm, K Takata, E Casey, O Mary, J Meyerson, K Gaynor, J LaFrancois, L Wang and T Kondo et al., Neuron 38 (2003), pp. 555–565. Article |

PDF (454 K) | View Record in Scopus | Cited By in Scopus (188)

Patrick et al. 1999 G.N Patrick, L Zukerberg, M Nikolic, S de la Monte, P Dikkes and L.H Tsai,Nature 402 (1999), pp. 588–589.

Pei et al. 1999 J.J Pei, E Braak, H Braak, I Grundke-Iqbal, K Iqbal, B Winblad and R.F Cowburn, J. Neuropathol. Exp. Neurol. 58 (1999), pp. 1010–1019. View Record in Scopus | Cited By in Scopus (234)

Phiel et al. 2003 C.J Phiel, C.A Wilson, V.M Lee and P.S Klein, Nature 423 (2003), pp. 435–439.View Record in Scopus | Cited By in Scopus (491)

Poorkaj et al. 1998 P Poorkaj, T.D Bird, E Wijsman, E Nemens, R.M Garruto, L Anderson, A Andreadis, W.C Wiederholt, M Raskind and G.D Schellenberg, Ann. Neurol. 43 (1998), pp. 815–825. View Record in Scopus | Cited By in Scopus (731)

Wittmann et al. 2001 C.W Wittmann, M.F Wszolek, J.M Shulman, P.M Salvaterra, J Lewis, M Hutton and M.B Feany, Science 293 (2001), pp. 711–714. View Record in Scopus | Cited By in Scopus (314)

Yamaguchi et al. 1996 H Yamaguchi, K Ishiguro, T Uchida, A Takashima, C.A Lemere and K Imahori, Acta Neuropathol. (Berl.) 92 (1996), pp. 232–241. View Record in Scopus | Cited By in Scopus (147)

Zheng et al. 2002 W.H Zheng, S Bastianetto, F Mennicken, W Ma and S Kar, Neuroscience 115(2002), pp. 201–211. Abstract | Article |

PDF (493 K) | View Record in Scopus | Cited By in Scopus (68)

Correspondence: Daniel H. Geschwind, 310-206-6814 begin_of_the_skype_highlighting 310-206-6814 end_of_the_skype_highlighting (phone), 310-267-2401 (fax)

Morphological Types of Glial Tangles and Related Structures

Volume 88, Number 2, 113-121, DOI: 10.1007/BF00294503

REGULAR PAPER

Corticobasal degeneration: a disease with widespread appearance of abnormal tau and neurofibrillary tangles, and its relation to progressive supranuclear palsy

H. Mori, M. Nishimura, Y. Namba and M. Oda

Abstract

The neuropathological findings, including immunohistochemistry and electron microscopy, of two patients with clinical findings consistent with corticobasal degeneration (CBD) are reported. Both patients showed degeneration of the precentral cortex, the substantia nigra, the pallidum, and the thalamus. Many ballooned neurons were seen in the cerebral cortex, and argentophilic, skein-like inclusions suggesting neurofibrillary tangles (NFTs) were found in the brain stem and precentral cortex in patient 1. In contrast, patient 2 clearly showed NFTs in the brain stem and dentate nucleus which were indistinguishable from those seen in progressive supranuclear palsy (PSP), while only a few ballooned neurons were found in the cerebral cortex. Gallyas silver stain showed many argentophilic inclusions suggesting NFTs in the brain stem, subcortical nuclei, and cerebral cortex in both patients. Immunohistochemistry for tau showed tau-positive neurons in the cerebral cortex, brain stem, subcortical nuclei and spinal cord, and tau-positive glial cells were seen in the cerebral cortex, white matter and subcortical nuclei, and thread-like structures were seen in the cerebral cortex and white matter. Electron microscopy of the brain stem showed NFTs consisting of paired helical filaments in patient 1, and paired helical filaments and straight tubules in patient 2. Immunoelectron microscopy revealed parallel tau-positive filaments in the cerebral cortex in patent 1. From the two patients, the widespread appearance of abnormal tau and NFTs is one of the essential pathological features in CBD, and it also appears that CBD and PSP have some common underlying pathological processes. Patient 2 is closer to PSP than patient 1 and suggests CBD would link to PSP.

Key words Corticobasal degeneration - Progressive supranuclear palsy - Neurofibrillary tangles - Abnormal tau

Fulltext Preview

Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders

Dr Catharine L. Joachim MD^1,2,*,

James H. Morris BM, BCH, PhD²,

Kenneth S. Kosik MD¹,

Dennis J. Selkoe MD¹

Article first published online: 8 OCT 2004

DOI: 10.1002/ana.410220411

Abstract

Neurofibrillary tangles occur in a number of apparently distinct neurodegenerative diseases and in normal aging of the human brain. Antibodies raised against Alzheimer's disease paired helical filaments immunolabel the tangles seen in all other tangle-associated disorders examined to date. The neuronal microtubule-associated protein, tau, has recently been identified as an antigenic component of neurofibrillary tangels and senile plaque neurites in Alzheimer's disease. Three different polyclonal antibodies with strong tau immunoreactivity are examined in this study. These antibodies were found to immunostain tangles in normal aged brain and in brains affected by a range of neurodegenerative disorders, including Down's syndrome, Alzheimer's disease plus Parkinson's disease, progressive supranuclear palsy, and the parkinsonism-dementia complex of Guam, as well as Pick bodies in Pick's disease. The findings further illustrate the relative nonspecificity of neurofibrillary lesions in neurodegenerative disorders.

Get PDF (1678K)

Catharine L. Joachim James H. Morris Kenneth S. Kosik Dennis J. Selkoe

Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert

Tobias Engel,

Paloma Goñi-Oliver,

José J. Lucas,

Jesús Avila,

Félix Hernández

Article first published online: 31 JUL 2006

DOI: 10.1111/j.1471-4159.2006.04139.x

Keywords:

Alzheimer's disease;

frontotemporal dementia and parkinsonim linked to chromosome 17;

glycogen synthase kinase-3;

lithium;

neurofibrillary tangles

Abstract

Glycogen synthase kinase-3 (GSK-3) has been proposed as the main kinase able to aberrantly phosphorylate tau in Alzheimer's disease (AD) and related tauopathies, raising the possibility of designing novel therapeutic interventions for AD based on GSK-3 inhibition. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations. Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression. We had previously generated a double transgenic model, overexpressing GSK-3β in a conditional manner, using the Tet-off system and tau protein carrying a triple FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation. This transgenic line shows tau hyperphosphorylation in hippocampal neurones accompanied by neurofibrillary tangles (NFTs). We used this transgenic model to address two issues: first, whether chronic lithium treatment is able to prevent the formation of aberrant tau aggregates that result from the overexpression of FTDP-17 tau and GSK-3β; second, whether lithium is able to change back already formed NFTs in aged animals. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Furthermore, it is still possible to partially reverse tau pathology in advanced stages of the disease, although NFT-like structures cannot be changed. The same results were obtained after shut-down of GSK-3β overexpression, supporting the possibility that GSK-3 inhibition is not sufficient to reverse NFT-like aggregates.

View Full Article (HTML) Get PDF (1004K

Brain Research
Volume 601, Issues 1-2, 22 January 1993, Pages 164-172

doi:10.1016/0006-8993(93)91707-Y \| How to Cite or Link Using DOI	Cited By in Scopus (56)
Permissions & Reprints

Lack of the car☐yl terminal sequence of tau in ghost tangles of Alzheimer's disease

Purchase

Riuko Endoh^a, Midori Ogawara^b, Takeshi Iwatsubo^a, Imaharu Nakano^cand Hiroshi Mori^,^a^,^b

^aDepartment of Neuropathology, Institute of Brain Research, University of Tokyo School of Medicine, Tokyo (Japan)

^bDepartment of Neurophysiology, Tokyo Metropolitan Institute of Gerontology, Tokyo (Japan)

^cDepartment of Neurophysiology, Tokyo Metropolitan Institute of Neuroscience, Tokyo (Japan)

Accepted 18 August 1992.

Available online 6 March 2003.

Using seven independent antibodies against the amino terminal to the car☐yl sequence of tau, we biochemically analyzed and compared the neuropathogenesis of two Alzheimer's disease brains from the viewpoint of abnormal processing on tau, the major constituent of paired helical filaments. One showed typical Alzheimer's disease with senile plaques and intracellular neurofibrillary tangles. The other showed advanced Alzheimer's disease with senile plaques and virtually the sole of ghost tangles without intracellular neurofibrillary tangles. We confirmed the previous observation that the car☐yl thirds of tau are tightly associated with paired helical filaments isolated in the presence of SDS. We found that biochemically, ghost tangles were abnormally phosphorylated and lacked the final car☐yl terminal sequence as well as the amino half of tau, unlike intracellular tangles. From these biochemical results taken together with the current evidence for ubiquitin in ghost tangles, we concluded that ghost tangles were extensively processed and irreversibly transformed into highly insoluble extracellular deposits.

Keywords: Tau; Ghost tangle; Alzheimer's disease; Processing; Abnormal phosphorylation

Correspondence: H. Mori, Department of Neuropathology, Institute of Brain Research, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113, Japan. Fax: (81) (813) 3814-8154.

Ultrastructural localization of beta-amyloid, tau, and ubiquitin epitopes in extracellular neurofibrillary tangles

M Tabaton,

S Cammarata,

G Mancardi,

V Manetto,

L Autilio-Gambetti,

G Perry, and

P Gambetti

+Author Affiliations

Department of Neurology, University of Genoa, Italy.

Abstract

Neurofibrillary tangles (NFTs), a hallmark of Alzheimer disease, are commonly located in perikarya of neurons. In advanced cases of Alzheimer disease, however, NFTs are observed also in the extracellular space. As extracellular NFTs (E-NFTs), and occasionally intracellular NFTs (I-NFTs), are recognized by antibodies to beta-amyloid protein (beta AP), beta AP may be present not only in amyloid deposits but also in paired helical filaments (PHFs), the primary components of NFTs. We compared the antigenic characteristics of I-NFTs and E-NFTs with light- and electron-microscopic immunocytochemistry by using several antibodies to noncontiguous epitopes of the microtubule-associated protein tau and of ubiquitin (Ub) as well as an antiserum to beta AP. At variance with I-NFTs, E-NFTs were made predominantly of straight filaments (SFs), rather than PHFs, that were often separated by astroglial processes and in close association with small beta AP deposits. Occasionally, E-NFTs were made of bundles of amorphous material, which showed no resemblance to SFs, PHFs, or amyloid fibrils. The antigenic changes in E-NFTs suggest that when NFTs become extracellular they lose the N and, possibly, the C termini of tau while maintaining the intermediate region of the molecule; they also lose the N-terminal two-thirds of Ub while the C-terminal conjugation site of Ub is preserved. A small subset of E-NFTs reacted with antibodies to both beta AP and tau. Although in most E-NFTs, the epitopes recognized by tau and Ub antibodies were located in typical PHFs and SFs, the epitopes recognized in this subset of anti-beta AP and anti-tau-positive E-NFTs were located exclusively in the bundles of amorphous material. It is suggested that either beta AP epitopes are present but inaccessible in PHFs and SFs and become exposed after conformational changes occurring in the extracellular space or PHFs and SFs become closely associated with beta AP in the extracellular space.

Neurobiology of Aging
Volume 19, Issue 1, Supplement 1, 2 January 1998, Pages S85-S91

doi:10.1016/S0197-4580(98)00034-7 \| How to Cite or Link Using DOI	Cited By in Scopus (58)
Permissions & Reprints

Original Articles

Glial Tau Pathology in Neurodegenerative Diseases: Their Nature and Comparison with Neuronal Tangles

Purchase

K. Ikeda^A^,^*, H. Akiyama^A, T. Arai^A and T. Nishimura^A

^A Department of Neuropathology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156, Japan

Available online 20 August 1998.

Abstract

Tau-positive inclusions that occur in glial cells are called glial fibrillary tangles or, more simply, glial tangles. These include tuft-shaped astrocytes, thorn-shaped astrocytes, coiled bodies, and argyrophilic threads. The latter two structures occur in oligodendroglia. The tau protein in glial tangles is hyperphosphorylated and has similar immunohistochemical profiles to that in neurofibrillary tangles (NFTs) except that there are no epitopes derived from alternatively spliced exon 2 and 3. In contrast to NFTs, glial tangles rarely show solid filaments. Such NFT-associated molecules as ubiquitin, apolipoprotein E, alpha1-antichymotrypsin, and heparan sulfate are all absent from glial tangles. These characteristics suggest that glial tangles resemble the pre-tangles that occur in neurons and are thought to represent an early stage of NFTs. Tau pathology in neurodegenerative diseases takes heterogenous forms.

Author Keywords: Glial tangles; Neurofibrillary tangles; Pre-tangles

Article Outline

Materials and Methods

Results

Tuft-Shaped Astrocytes and Related Structures

Thorn-Shaped Astrocytes and Related Structures

Coiled Bodies

Argyrophilic Threads

Immunohistochemical Characterization of Glial Tangles and Argyrophilic Threads

Morphological and Immunohistochemical Characterization of Pre-Tangles

Discussion

Volume 90, Number 6, 620-625, DOI: 10.1007/BF00318575

REGULAR PAPER

Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles

K. Ikeda, H. Akiyama, H. Kondo, C. Haga, E. Tanno, T. Tokuda and S. Ikeda

Download PDF (3.2 MB)

Abstract

Argyrophilic and tau-positive abnormal structures occurring in glial cells are called glial fibrillary tangles. In the astrocyte, a conspicuous tau-positive structure is known to appear in progressive supranuclear palsy (PSP). In this report, another type of argyrophilic and tau-positive astrocytes is reported. The morphology of this new type is quite different from that of the previously reported tau-positive astrocyte in PSP and they are designated here as thorn-shaped astrocytes (TSA). TSA have an apparently argyrophilic cytoplasm with a few short processes and often have a small eccentric nucleus, whose appearance resembles that of a reactive astrocyte. Immunohistochemically, TSA are positive to anti-tau antibodies but are negative for ubiquitin. Simultaneous immunostaining revealed the coexistence of tau and glial fibrillary acidic protein epitopes in the same cytoplasm. Electron microscopically, bundles of 15-nm straight tubules were included in the cytoplasm together with abundant glial filaments. In the vicinity of a cluster of TSA, related structures of perivascular or subpial tau-positive linings, which correspond to astrocytic end-feet, are sometimes observed. In almost all cases, a few TSA are generally located in a confined area of subpial and subependymal regions. Although TSA appear to be intimately associated with some diseases, they are also found in a wide range of cytoskeletal disorders including the aged brain with neurofibrillary tangles. TSA are presumed to be a secondarily induced product in relation to astrocytic reaction.

Key words Thorn-shaped astrocyte - Glial fibrillary tangles - Tau - Astrocyte - Straight tubules

Neurofibrillary Tangles in Progressive Supranuclear Palsy Contain the Same Tau Epitopes Identified in Alzheimer's Disease PHFtau

Schmidt, Marie Luise PhD; Huang, Richard BS; Martin, John A. BS; Henley, Jewel BS; Mawal-Dewan, Madhumalti PhD; Hurtig, Howard I. MD; -Y. Lee, Virginia M. PhD; Trojanowski, John Q. MD, PhD

Abstract

Neurofibrillary tangle (NFT)-rich brain samples from patients with progressive supranuclear palsy (PSP) or Alzheimer's disease (AD) were probed with a large panel of anti-tau antibodies to compare the species of tau present in PSP and AD NFTs by immunohistochemistry and Western blot methods. These antibodies have been shown to recognize phosphate-independent or -dependent epitopes that extend from the amino to the carboxy terminal domains of normal brain tau and the abnormal tau in the paired helical filaments (PHFs) of AD NFTs (PHFtau). The immunohistochemical studies showed that all of the tau epitopes detected in brainstem PSP NFTs also were found in hippocampal AD NFTs and vice versa. While Western blots demonstrated 2 PHFtau-like immunobands in PSP brainstem, a triplet of PHFtau proteins were seen in the AD and PSP hippocampus.

Despite differences in the distribution, ultrastructure and immunoblot profile of NFTs in PSP and AD, the same constellation of tau epitopes is present in the abnormal tau proteins in PSP and AD NFTs. Thus, the generation of abnormal tau proteins in PSP (PSPtau) and AD (PHFtau) may have similar adverse biological consequences in both diseases.

Neuroscience Letters
Volume 171, Issues 1-2, 25 April 1994, Pages 1-4

Abnormally phosphorylated tau protein related to the formation of neurofibrillary tangles and neuropil threads in the cerebral cortex of sheep and goat

Purchase

Heiko Braak^,^a, Eva Braak^a and Martin Strothjohann^a

^aDepartment of Anatomy, J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, FRG

Received 31 January 1994;

accepted 14 February 1994.

Available online 5 March 2003.

Abstract

Frontal sections including temporal isocortex, entorhinal region and hippocampus from aged domestic animals (dog, cat, horse, sheep and goat) were studied for Alzheimer-related changes using immunostaining with the AT8 antibody for abnormally phosphorylated tau protein and selective silver techniques for A4 amyloid and neurofibrillary changes of the Alzheimer type. The material available to us did not show A4 amyloid deposits or argyrophilic neurofibrillary changes. Only the brains of aged sheep and goat exhibited the presence of AT8-immunoreactive pyramidal cells in the entorhinal region and hippocampal formation. Two groups of AT8-positive neurons could be observed: The first group contained evenly distributed immunoreactive material in all parts of the soma, the dendrites and the axon. The neuronal processes appeared quite normal. The second group, however, showed conspicuous changes in the cellular processes consisting of a loss of immunoreactivity within the axon and the proximal dendrites and the appearance of intensely stained swellings within the curved distal dendrites. These changes were closely reminiscent to alterations of the cytoskeleton known to occur at the same location in the aging human brain and in Alzheimer's disease. The findings justify a closer look at sheep and goat when searching for suitable animal models for experimental studies of the conditions responsible for the development of Alzheimer-related neurofibrillary changes.

Keywords: Animal model; Alzheimer's disease; Cytoskeleton; Neurofibrillary change; Tau protein; Abnormal phosphorylation

Corresponding author: Fax: (49) 69-6301-6425.

Microscopy and image capture

Volume 84, Number 6, 596-605, DOI: 10.1007/BF00227736

Immunocytochemistry of neurofibrillary tangles with antibodies to subregions of tau protein: identification of hidden and cleaved tau epitopes and a new phosphorylation site

D. W. Dickson, H. Ksiezak-Reding, W. -K. Liu, P. Davies, A. Crowe and S. -H. C. Yen

Abstract

Antibodies to multiple epitopes spanning the length of the tau molecule were used to study Alzheimer neurofibrillary tangles (NFT) using immunocytochemical methods and several differnt methods of fixation and tissue processing, including staining of vibratome sections, hydrated autoclaving of paraffin sections and immunofluorescence of NFT isolated from fresh brain tissue. Smears and sections were pretreated with trypsin and/or phosphatase to further characterize antibody binding. In tissue fixed briefly in periodate-lysine-paraformaldehyde, tau immunoreactivity was detected in astrocytes, but only a few tau epitopes were detected in NFT with this fixation method. In contrast, all tau epitopes were detected in NFT in tissue fixed in formaldehyde for prolonged periods of time. In the hippocampus, the number of NFT detected in the dentate fascia was in proportion to the duration of dementia, as we previously noted. Dentate fascia NFT were intracellular (i-NFT) and were reactive with antibodies recognizing epitopes in both the carboxy- and amino-terminal regions of tau, but not the microtubule-binding domain of tau, suggesting that microtubule-binding domain epitopes are hidden in i-NFT. In contrast, NFT in the subiculum and layer II of the parahippocampal cortex were mostly extracellular (e-NFT), especially in severe cases of long duration, e-NFT were immunoreactive with antibodies to the microtubule-binding domain, but only weakly reactive with antibodies to carboxy- or amino-terminal epitopes, suggesting that e-NFT may contain fragments of tau. In both isolated NFT and NFT in sections, amino-terminal epitopes, including the Alz-50 epitope, were sensitive to trypsin proteolysis, which suggests that the lack of staining of e-NFT by antibodies to the amino-terminal regions of tau is due to proteolysis. Antibodies reactive with amino-terminal epitopes also stained fewer NFT following hydrated autoclaving, while those reacting with the carboxy half of tau stained more NFT after hydrated autoclaving. Thus, although carboxy-terminal regions are not detected in e-NFT, they are probably masked, rather than proteolytically cleaved, since they can be revealed by hydrated autoclaving. Finally, phosphatase treatment of isolated NFT revealed enhanced immunostaining not only with Tau-1, as in previous studies demonstrating abnormal phosphorylation of tau proteins in NFT, but also with an antibody to exon 2, which reveals yet another phosphorylation site in tau of NFT.

Key words Alzheimer's disease - Immunocytochemistry - Neurofibrillary tangles - Paired helical filaments - Tau protein

Supported by NIA AG06803, AG01136 and AG04145

Neurochemistry International
Volume 40, Issue 1, January 2002, Pages 17-30

doi:10.1016/S0197-0186(01)00061-4 \| How to Cite or Link Using DOI

Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer's disease

Purchase

Steven M. Singer^a, Gina M. Zainelli^a, Maryam A. Norlund^a, John M. Lee^a^,^b and Nancy A. Muma^,^,^a

^a The Department of Pharmacology, Loyola University Medical Center, 2160 S First Avenue, Maywood, IL 60153, USA

^b The Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA

Available online 1 December 2001.

Abstract

Transglutaminase-catalyzed

(γ-glutamyl)lysine cross-links exist in Alzheimer's disease (AD) paired helical filament (PHF) tau protein but not normal soluble tau. To test the hypothesis that these cross-links could play a role in the formation of neurofibrillary tangles (NFT), we used single- and double-label immunofluorescence confocal microscopy and immunoaffinity purification and immunoblotting to examine

(γ-glutamyl)lysine cross-links in AD and control brains. The number of neurons that are immunoreactive with an antibody directed at the

-(γ-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with

(γ-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains

(γ-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II,

(γ-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with

(γ-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.

Author Keywords: Alzheimer's disease; Cross-linking; Neurofibrillary tangle; Paired helical filament; Tauopathy; Transglutaminase

Abbreviations: AD, Alzheimer's disease; Mab, monoclonal antibody; NFT, neurofibrillary tangles; PHF, paired helical filaments

Article Outline

Introduction

Experimental procedures

Double-label immunofluorescence

Fluorescence and confocal microscopy

Protein isolation

Immunoaffinity purification

Western blots

Results

Neuronal

-(γ-glutamyl)lysine cross-links in cortical and cervical spinal cord tissue

Confocal localization of

-(γ-glutamyl)lysine cross-links with PHF-Tau in NFTs

Immunocytochemistry characterization experiments

-(γ-glutamyl)lysine cross-links in PHF tau in AD cortex

Cross-linking of PHF tau is an early phenomenon

Discussion

Am J Pathol. 1990 May; 136(5): 1069–1075.

PMCID: PMC1877428

Relative abundance of tau and neurofilament epitopes in hippocampal neurofibrillary tangles.

M. L. Schmidt, V. M. Lee, and J. Q. Trojanowski

Department of Pathology and Laboratory Medicine (Neuropathology), University of Pennsylvania School of Medicine, Philadelphia 19104-4283.

Neurofibrillary tangles (NFTs) derive, in part, from normal neuronal cytoskeletal proteins, ie, large portions of tau (tau) but only restricted segments of the peripheral domains of the high- and middle-molecular weight neurofilament subunits. To learn more about the events leading to the incorporation of tau and neurofilament epitopes into NFTs, the relative abundance of tau and NF determinants in these lesions was quantitatively analyzed in hippocampi from Alzheimer disease (AD) patients and age-matched controls using monoclonal antibodies specific for tau or for NF proteins. Immunostained NFTs appeared qualitatively the same in both AD and controls, ie, every epitope found in AD NFTs occurred also in the NFTs of the control patients. However, in hippocampi with only a few tangles, tau epitopes, but no NF epitopes, were detected in NFTs. In contrast, both tau and NF epitopes were present in those tangles that were found in hippocampi with abundant NFTs. Nevertheless, the number of tau-positive NFTs generally exceeded the number of NF-positive NFTs. These findings indicate that tau epitopes are more abundant than NF epitopes in NFTs and that the formation of NFTs may be linked to a derangement in the normal metabolism of tau that is more extensive than alterations in NF protein metabolism.

Volume 88, Number 6, 592-598, DOI: 10.1007/BF00296499

CASE REPORTS

Unusual case of corticobasal degeneration with tau/Gallyas-positive neuronal and glial tangles

Abstract

A 74-year-old woman with corticobasal degeneration (CBD) had a 9-year history of progressive loss of strength and rigidity of her right hand and then arm, followed by speech difficulties, dyskinesia, rigidity, spasticity and weakness of the ipsilateral lower limb, ultimately also involving the apposite side. She later developed supranuclear gaze palsy. Her memory remained intact during most of the duration of her disease. Laboratory tests and anti-Parkinsonian medications were not helpful. At autopsy, frontal lobe atrophy, discoloration of putamen (Pt) and pallor of substantia nigra (Sn) were observed. Neuronal loss and gliosis were extensive in motor cortex and milder in frontal cortex, abruptly ending at the central sulcus and junction of cingulate gyrus.

Achromatic

neurons were present. Neuronal loss and gliosis were seen in Pt and Sn and corticobasal inclusions in Sn. Numerous Gallyas/tau-positive, Bielschowsky/ubiquitin-negative coil, sickle, or coma-shaped tangles and thread-like processes were found in affected cortex, Pt and Sn. Some of the tangles were in neurons, but most occurred in astroglia, and their processes. The presence of Gallyas/tau-positive glia in CBD may have the same diagnostic significance as in progressive supranuclear palsy, analogous to the argyrophilic ubiquinated inclusions in oligodendroglia in multisystem atrophy. We suggest that in CBD: (1) cytoskeletal protein metabolism in neurons and glia can simultaneously be perturbed in certain neurodegenerative diseases, and (2) the astrocytosis in CBD may not be simply a reactive process but an integral part of the disease.

The role of tau filaments in neurodegenerative disease

Volume 77, Number 4, 430-436, DOI: 10.1007/BF00687379

REGULAR PAPERS

Senile plaque neurites fail to demonstrate anti-paired helical filament and anti-microtubule-associated protein-tau immunoreactive proteins in the absence of neurofibrillary tangles in the neocortex

Probst, B. H. Anderton, J. -P. Brion and J. Ulrich

Abstract

Although much work has been directed recently towards unravelling the protein chemistry of neurofibrillary tangle (NFT) and senile plaque (SP) components in Alzheimer's disease, the pathogeneses of these lesions remains largely unknown and the problem of their relationship is unresolved. In particular, although paired helical filaments (PHF) have long been documented in SP neurites, we do not know if they are of pathogenetic relevance for the formation of the SP. To investigate the relationship between NFT and SP, we examined antigenic properties of proteins in SP neurites in neocortical tissues of patients with senile dementia of Alzheimer type, in the presence or absence of NFT in the same cortical area. We used two polyclonal antibodies directed against PHF and microtubule-associated protein (MAP)-tau and three monoclonal antibodies (MAbs) (RT97, BF10, 147) to phosphorylated epitopes of human neurofilament polypeptides, as well as the Gallyas silver impregnation method which specifically stains PHF in NFT and neurites. The main finding of our investigations consists in a differential pattern of immunoreactivity of SP neurites depending on the presence or absence of NFT in the neocortex. In the presence of NFT, there were numerous neuropil threads and SP neurites containing Gallyas-positive, as well as anti-PHF- and anti-tau-labelled material. In the absence of NFT in the neocortex there was a striking absence of any Gallyas-positive or PHF- and tau-immunoreactive structure in the cortical neuropil and in SP neurites, irrespective of the maturation stage of the SP. In contrast with these results, the number of neurites labelled by MAbs RT97, BF10 and 147 in SP and in the neuropil was apparently unaffected by the presence or absence of NFT. Amyloid in SP, remained consistently unstained by all antibodies of the panel as well as by the Gallyas stain. Our findings indicate that PHF and tau polypeptides are facultative components of SP neurites and suggest that the development of SP may occur independently of PHF pathology in neocortical neurons.

Key words Senile plaque - Paired helical filaments - Microtubule-associated (MAP)-tau protein - Neurofibrillary tangles - Alzheimer

Supported by the Wellcome Trust and the Medical Research Council

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Volume 1739, Issues 2-3, 3 January 2005, Pages 216-223
The Biology and Pathobiology of Tau

doi:10.1016/j.bbadis.2004.08.014 \| How to Cite or Link Using DOI

Review

Tau, tangles, and Alzheimer's disease

Purchase

Lester I. Binder^a^,^b^,^,, Angela L. Guillozet-Bongaarts^a^,^b, Francisco Garcia-Sierra^c and Robert W. Berry^a^,^b

^aDepartment of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, United States

^bCognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, United States

^cDepartment of Cell Biology, Center of Research and Advanced Studies of the National Polytechnic Institute, Av. Instituto Politecnico Nacional 2508, CP 07360, Mexico City, Mexico

Received 30 August 2004;

accepted 31 August 2004.

Available online 15 September 2004.

Abstract

Keywords: Neurofibrillary tangle; Tau; Alzheimer's disease

Article Outline

Introduction

Tau conformation and tangle formation

The role of the amino-terminus in tau filament formation

The role of the carboxy-terminus in tau filament formation

Caspases may cause carboxy and amino truncations of tau in situ

Carboxy truncation and cellular toxicity

The evolution of tau structure within NFTs

Conclusion and unanswered questions