Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms

“A number of studies have detected DNA fragmentation, a hallmark of apoptosis, in AD tissue sections using the terminal deoxynucleotide transferase mediated dUTP nick-end labeling (TUNEL) method (Gavrieli et al., 1992; Sgonc and Wick, 1994) to identify 3 -OH ends of broken DNA (Su et al.”

“However, no mutations have been found in the tau gene in AD, and the relationship between tau pathology, amyloid deposition, and neuronal degeneration is difficult to determine (Hardy and Higgins, 1992; Taylor et al., 2002).”

“…life in specific brain regions, including the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus (Eriksson et al., 1998; Gould et al., 1998), but it does not normally occur in most regions with large populations of postmitotic neurons.”

“These pathways are classically grouped based on stereotyped changes in nuclear morphology (Kerr, 1972; Leist and Jaattela, 2001), principally with respect to chromatin condensation, and on the presence or absence of the classic cell executioners: the caspases (for review, see Hengartner, 2000).”

“Mutations in the tau gene have been linked to NFT formation in a number of tauopathies in which no -amyloid deposits develop (Hutton et al., 1998; Spillantini et al., 1998; Poorkaj et al., 2001).”

“The optical fractionator (West et al., 1991) was used to obtain quantitative estimates of neuronal loss with age in the htau mice.”

“These pathways are classically grouped based on stereotyped changes in nuclear morphology (Kerr, 1972; Leist and Jaattela, 2001), principally with respect to chromatin condensation, and on the presence or absence of the classic cell executioners: the caspases (for review, see Hengartner, 2000).”

“Moreover, there is evidence to suggest that some neurons in AD brain may die without forming NFTs (Gomez-Isla et al., 1997).”

“Mutations in the tau gene have been linked to NFT formation in a number of tauopathies in which no -amyloid deposits develop (Hutton et al., 1998; Spillantini et al., 1998; Poorkaj et al., 2001).”

“…life in specific brain regions, including the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus (Eriksson et al., 1998; Gould et al., 1998), but it does not normally occur in most regions with large populations of postmitotic neurons.”

“However, no mutations have been found in the tau gene in AD, and the relationship between tau pathology, amyloid deposition, and neuronal degeneration is difficult to determine (Hardy and Higgins, 1992; Taylor et al., 2002).”

“Tau isoforms can be separated into two groups, either 3R or 4R, depending on the inclusion or exclusion of exon 10 (Goedert et al., 1988, 1989; Lee et al., 1988; Himmler, 1989).”

“PCNA is a cell-cycle regulatory molecule that appears to play a coordinating role in a number of interactions at the DNA replication fork but has also been shown to be involved in DNA repair (for review, see Maga and Hubscher, 2003).”

“Tau isoforms can be separated into two groups, either 3R or 4R, depending on the inclusion or exclusion of exon 10 (Goedert et al., 1988, 1989; Lee et al., 1988; Himmler, 1989).”

“Neurodegeneration has been demonstrated to occur without NFT formation in a Drosophila model of tauopathy in which wild-type human tau is expressed (Wittmann et al., 2001), although the extent of neurodegeneration was much higher in flies expressing mutant (R406W) human tau.”

“The amount of ki67 is normally tightly regulated (Scholzen and Gerdes, 2000), and, although its exact function in the cell cycle is not known, it has been determined to be essential for cell proliferation (Schluter et al., 1993) and is aberrantly expressed in AD (Nagy et al., 1997).”

“Ultracentrifugation and Sarkosyl extraction (30 min incubation in 1% Sarkosyl) was performed according to Greenberg and Davies (1990) to obtain insoluble fractions of tau from htau mice aged 15 months.”

“E) (Andorfer et al., 2003), whereas many neurons with tau aggregates displayed intact nuclei (Fig.”

“Alterations in the ratio of 3R and 4R isoforms, normally equal in humans, have been linked to a number of neurodegenerative diseases that develop NFTs (Spillantini and Goedert, 1998; Hutton, 2001; Poorkaj et al., 2001).”

“Tau isoforms can be separated into two groups, either 3R or 4R, depending on the inclusion or exclusion of exon 10 (Goedert et al., 1988, 1989; Lee et al., 1988; Himmler, 1989).”

“…could be related to a disruption of axonal transport, which has been shown to cause cell death in several animal models (Gunawardena and Goldstein, 2001; LaMonte et al., 2002; Gunawardena et al., 2003) and has been suggested as a potential cause of neurodegeneration in AD (Goldstein, 2003).”

“DOI:10.1523/JNEUROSCI.4637-04.2005 Copyright © 2005 Society for Neuroscience 0270-6474/05/255446-09$15.00/0 regions in which cell death is extensive (Lew et al., 1995; Busser et al., 1998; Yang et al., 2001, 2003; Herrup and Arendt, 2002).”

“However, of these studies, some groups have detected morphological changes consistent with apoptosis (Su et al., 1994; Cotman and Anderson, 1995), whereas other groups have not (Lassmann et al.”

“Mice expressing a cDNA for the shortest 3R isoform of tau (Ishihara et al., 1999) also develop tau pathology at high age (2 years), although the pathology is not obviously accompanied by neurodegeneration.”

“, 2004) because overstabilization (Jordan et al., 1996; Yvon et al., 1999) and destabilization (Jordan et al.”

“DOI:10.1523/JNEUROSCI.4637-04.2005 Copyright © 2005 Society for Neuroscience 0270-6474/05/255446-09$15.00/0 regions in which cell death is extensive (Lew et al., 1995; Busser et al., 1998; Yang et al., 2001, 2003; Herrup and Arendt, 2002).”

“…could be related to a disruption of axonal transport, which has been shown to cause cell death in several animal models (Gunawardena and Goldstein, 2001; LaMonte et al., 2002; Gunawardena et al., 2003) and has been suggested as a potential cause of neurodegeneration in AD (Goldstein, 2003).”

“1B) resembled reactivity of these antibodies to NFTs from human brain (Fig.”

“NFT-like formation and cell death from tau with no mutations has been shown in a Drosophila model combining overexpression of wild-type human tau with manipulation of GSK3 (glycogen synthase kinase-3 ) activation (Jackson et al., 2002).”

“DOI:10.1523/JNEUROSCI.4637-04.2005 Copyright © 2005 Society for Neuroscience 0270-6474/05/255446-09$15.00/0 regions in which cell death is extensive (Lew et al., 1995; Busser et al., 1998; Yang et al., 2001, 2003; Herrup and Arendt, 2002).”

“, 2000), with tau knock-out (KO) mice that have a targeted disruption of exon one of tau (Tucker et al., 2001).”

“Cells in htau brains show evidence of DNA fragmentation but no activation of caspases DNA fragmentation can be detected using the TUNEL method (Gavrieli et al., 1992; Sgonc and Wick, 1994) to label broken 3 -”

“Cyclin D1 is another cell-cycle regulating molecule that is involved in controlling the progression of the cell cycle through G1-phase to the boundary of the S-phase (for review, see Coqueret, 2002).”

“This axonal pathology could be related to a disruption of axonal transport, which has been shown to cause cell death in several animal models (Gunawardena and Goldstein, 2001; LaMonte et al., 2002; Gunawardena et al., 2003) and has been suggested as a potential cause of neurodegeneration in AD…”

“The 3R isoforms of tau have been shown to have a lower affinity for microtubules (Goode and Feinstein, 1994; Panda et al., 1995) and a differential ability to regulate microtubule dynamics (Panda et al.”

“Cells in htau brains show evidence of DNA fragmentation but no activation of caspases DNA fragmentation can be detected using the TUNEL method (Gavrieli et al., 1992; Sgonc and Wick, 1994) to label broken 3 -”

“Changes in microtubule behavior have been shown to activate programmed cell-death signals (Srivastava et al., 1998; Giannakakou et al., 2001; Ye et al., 2001) (for review, see Michaelis et al.”

“Tau isoforms can be separated into two groups, either 3R or 4R, depending on the inclusion or exclusion of exon 10 (Goedert et al., 1988, 1989; Lee et al., 1988; Himmler, 1989).”

“The amount of ki67 is normally tightly regulated (Scholzen and Gerdes, 2000), and, although its exact function in the cell cycle is not known, it has been determined to be essential for cell proliferation (Schluter et al., 1993) and is aberrantly expressed in AD (Nagy et al., 1997).”

“, 1997a,b, 1999) that is specific to abnormal tau (Weaver et al., 2000); and (3) PHF1 (paired helical filament), specific for phosphorylation at serines 396/404 (Ps396/ 404), reacting with later-stage NFTs (Otvos et al.”

“Involvement of cell-cycle mechanisms in the neuronal death that follows hypoxia-ischemia has also been suggested in two recent papers (Kuan et al., 2004; Wen et al., 2004).”

“, 1995) and a differential ability to regulate microtubule dynamics (Panda et al., 2003; Bunker et al., 2004).”

“The coefficient of error was calculated according to Schmitz and Hof (2000).”

“, 2003) by crossing mice that express a tau transgene derived from a human PAC, H1 haplotype, termed 8c mice (Duff et al., 2000), with tau knock-out (KO) mice that have a targeted disruption of exon one of tau (Tucker et al.”

“Changes in microtubule behavior have been shown to activate programmed cell-death signals (Srivastava et al., 1998; Giannakakou et al., 2001; Ye et al., 2001) (for review, see Michaelis et al.”

“Still other groups have found evidence in AD tissue, suggesting that the mode of cell death is necrotic (Lucassen et al., 1997; Stadelmann et al., 1998).”

“Attempts to discriminate whether the mode of cell death in AD is necrotic or apoptotic have yielded mixed results, with fea- tures of each pathway having been detected via a variety of biochemical and histological approaches (for review, see Behl, 2000).”

“The 3R isoforms of tau have been shown to have a lower affinity for microtubules (Goode and Feinstein, 1994; Panda et al., 1995) and a differential ability to regulate microtubule dynamics (Panda et al.”

“Membranes were additionally probed with an antibody to SNAP-25 [synaptosome-associated protein of 25 kDa (SP-14)] (Honer et al., 1992) diluted 1:20 in 5% milk/1 TBS.”

“1B) resembled reactivity of these antibodies to NFTs from human brain (Fig.”

“, 1995) and a differential ability to regulate microtubule dynamics (Panda et al., 2003; Bunker et al., 2004).”

“Involvement of cell-cycle mechanisms in the neuronal death that follows hypoxia-ischemia has also been suggested in two recent papers (Kuan et al., 2004; Wen et al., 2004).”

“Still other groups have found evidence in AD tissue, suggesting that the mode of cell death is necrotic (Lucassen et al., 1997; Stadelmann et al., 1998).”

“A number of studies have detected DNA fragmentation, a hallmark of apoptosis, in AD tissue sections using the terminal deoxynucleotide transferase mediated dUTP nick-end labeling (TUNEL) method (Gavrieli et al., 1992; Sgonc and Wick, 1994) to identify 3 -OH ends of broken DNA (Su et al.”

“Cells in htau brains show evidence of DNA fragmentation but no activation of caspases DNA fragmentation can be detected using the TUNEL method (Gavrieli et al., 1992; Sgonc and Wick, 1994) to label broken 3 -”

“Immunohistochemistry Abnormal phosphorylation and conformational changes on tau can be detected with monoclonal antibodies, including the following: (1) CP13, reactive with phosphorylation on serine 202 on tau in pretangles (Kimura et al., 1996) and later-stage NFTs (Augustinack et al.”

“Alterations in the ratio of 3R and 4R isoforms, normally equal in humans, have been linked to a number of neurodegenerative diseases that develop NFTs (Spillantini and Goedert, 1998; Hutton, 2001; Poorkaj et al., 2001).”

“DOI:10.1523/JNEUROSCI.4637-04.2005 Copyright © 2005 Society for Neuroscience 0270-6474/05/255446-09$15.00/0 regions in which cell death is extensive (Lew et al., 1995; Busser et al., 1998; Yang et al., 2001, 2003; Herrup and Arendt, 2002).”

“Incubation and mounting were performed at pH 4.0 to quench enhanced green fluorescent protein fluorescence (Nakanishi et al., 2001).”

“…could be related to a disruption of axonal transport, which has been shown to cause cell death in several animal models (Gunawardena and Goldstein, 2001; LaMonte et al., 2002; Gunawardena et al., 2003) and has been suggested as a potential cause of neurodegeneration in AD (Goldstein, 2003).”

“Changes in microtubule behavior have been shown to activate programmed cell-death signals (Srivastava et al., 1998; Giannakakou et al., 2001; Ye et al., 2001) (for review, see Michaelis et al., 2002).”

“Zehr et al. (2004) have reported evidence of apoptosis in oligodendrocytes of mutant human tau transgenics, and we cannot exclude the possibility that the TUNEL-positive cells detected in htau mice were glia rather than neurons.”

“These pathways are classically grouped based on stereotyped changes in nuclear morphology (Kerr, 1972; Leist and Jaattela, 2001), principally with respect to chromatin condensation, and on the presence or absence of the classic cell executioners: the caspases (for review, see Hengartner, 2000).”

“DOI:10.1523/JNEUROSCI.4637-04.2005 Copyright © 2005 Society for Neuroscience 0270-6474/05/255446-09$15.00/0 regions in which cell death is extensive (Lew et al., 1995; Busser et al., 1998; Yang et al., 2001, 2003; Herrup and Arendt, 2002).”

“Changes in microtubule behavior have been shown to activate programmed cell-death signals (Srivastava et al., 1998; Giannakakou et al., 2001; Ye et al., 2001) (for review, see Michaelis et al.”

“Immunoblotting Immunoblotting was performed as described previously (Andorfer and Davies, 2000).”

“Such a cell-cycle-driven mechanism of neurodegeneration has been proposed to occur in AD and several other tauopathies (Herrup and Yang, 2001; Yang et al., 2001, 2003) (for review see, Vincent et al.”

“[84] showed that in human tau transgenic mice, while there was widespread neurodegeneration, the PHF-containing neurons, however, appeared “healthy” in terms of nuclear morphology, suggesting that the polymerization of hyperphosphorylated tau into fibrils was probably neuroprotective [84].”

“In transgenic mice overexpressing normal human tau, there are also signs of re-entry: tau accumulation could thus be the cause of the re-entry rather than its consequence [12].”

“A recent study has shown that tangles continue to form in tau-expressing transgenic mice even after tau expression is switched off, suggesting that soluble, rather than aggregated, tau species are neurotoxic, a view supported by the apparent dissociation between the number of tangles and the extent of neuronal death i…”