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).”

“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).”

“…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.”

“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).”

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

“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).”

“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).”

“, 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.”

“, 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.”

“, 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).”

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

“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.”

“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).”

“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).”

“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).”

“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.”

“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).”

“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…”

“Most recent studies of this model suggest the mechanism of tau-mediated neuronal death may involve the re-expression of cell-cycle proteins, indicating incomplete re-entry of the cell cycle (Andorfer et al., 2005).”

“, 2003) and neurodegeneration (Andorfer et al., 2005).”

“3C), suggest that deficiency of microglial CX3CR1 in hTauCx3cr1 / mice induces neurodegeneration, which occurs several months prior to significant neuronal loss demonstrated in the hTau mice (12 months versus 17 months of age) (Andorfer et al., 2005).”

“Cell death and synaptic lesions occur independently of formation of NFTs in h-tau mice expressing non-mutant human tau [13,14].”

“[11] 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 [11].”

“Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders.”

“[140].”

“In that model as well as in the htau model, region-specific dissociation of neuronal loss and neurofibrillary pathology has been observed (Andorfer et al., 2005; Spires et al., 2006), which suggests toxic effects of early stage pathological tau conformers that cannot easily be detected, analogous to A oligomers.”

“Neuronal cell death also occurred independently of histologically observed tangles in mice that express all six isoforms of wild-type human tau (Andorfer et al., 2005).”

“Likewise, many of the neurons that accumulate NFT in aged transgenic mice overexpressing normal htau seem "healthy" in terms of nuclear morphology, while a number of dying neurons do not appear to have a significant load of tau filaments [69].”

“Cell death in htau mice does not seem to be directly caused by the NFTs but appears to be linked to reexpression of proteins involved in cell-cycle and DNA synthesis [7].”

“Even the htau model overexpressing wild-type human MAPT was initially described with notable neuronal loss, albeit at much later ages (~17 months) [42], and may have since waned with successive generations of breeding (see “Neurofibrillary tangles” section for more detail).”

“Similarly, although wild-type human tau can show substantial toxicity when expressed in transgenic mic”

“In Drosophila and mouse models, overexpression of wild- type human tau induces neurodegeneration (Wittmann et al., 2001), axonopathy (Spittaels et al., 1999), and extensive cell death (Andorfer et al., 2005) independently of tangle formation.”

“These mice exhibit tau pathology in neurons of the neocortex and hippocampus in patterns similar to that occurring in NFTs of human brain and exhibited overt neuronal loss (Andorfer et al., 2003, 2005).”

“In support of this concept, transgenic mice carrying human tau mutations develop a late-onset neurodegenerative phenotype that includes neuronal loss (Andorfer et al., 2005; Ramsden et al., 2005).”

“Characteristic neuropathological findings include selective neuronal and synaptic losses (Morrison and Hof, 1997), extracellular neuritic plaques containing the b-amyloid peptide (Glenner and Wong, 1984; Masters et al., 1985) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated forms of the tau protein (…”

“Given the fact that neurons with NFT can survive for decades, which is consistent with data in mouse model that NFTs are not involved in neuronal death [120,121], it is tempting to suggest that the formation of neurofibrillary pathology is a further neuronal adaptation to chronic oxidative stress [122].”

“…mice develop tau pathology in an age-dependent manner We confirmed by immunohistochemistry that all htau animals from the two age groups exhibited an age-dependent tau pathology with very similar features to those present in human AD cases, as previously reported (Andorfer et al., 2003, 2005).”

“Interestingly, hallmarks of both apoptotic and necrotic cell death have been recently identified in neurons from transgenic mice expressing nonmutant forms of human tau (53).”

“These mice also develop neurodegeneration and age-dependent memory loss [72, 73].”

“beginning at approximately 6 months of age [25, 26].”

“In mice, two approaches have been followed to mimic the AD [55] or FTDP17 (see for example [56,57]) tauopathies.”

“CP13 is commonly used to detect tau pathology in both early (pre-tangles) and more advanced stages of NFT accumulation, whereas PHF1 is a marker for later stage tangles [1, 2].”

“Accumulating evidence suggests that CCE in neurons may precede tau and amyloid pathology, and that there is a link between CCE and tau-hyperphosphorylation (Andorfer et al., 2005; Park et al., 2007; Jaworski et al., 2009).”

“2009) and recent evidence that NFTs in experimental models do not directly correlate with neuron loss (Andorfer et al. 2005; SantaCruz et al. 2005) suggests that affected neurons may be able to withhold NFT formation for a long time before they degenerate.”

“The htau model (Jackson Laboratories, stock #004808) (Andorfer et al., 2005) was crossed with a model that expresses the PS1 M146L human mutation (Duff et al., 1996).”

“The issue of causality has previously been unresolved, although important studies have documented aberrant neuronal cell-cycle markers in human tauopathies and, more recently, in a mouse tauopathy model [36].”

“These and other data argue that synaptic deficits occur in an NFT-independent manner, again making the case that soluble tau serves as the toxic entity [51, 52, 56, 70, 92, 118].”

“Ectopic expression of cell-cycle markers in postmitotic neurons and their coincidence with tau pathology is a well-described feature of tauopathies [15, 16], and abnormal activation of the cell cycle in neurons can drive apoptosis in tau-transgenic Drosophila [6].”

“As a step forward, we suggest that more work should be performed using the Htau model which lacks murine tau [4], but in which both 3R and 4R human tau are spliced and translated, albeit in a different ratio than observed in either humans or mice.”

“For example, in mice that overexpress wild-type human tau, extensive neuronal death occurred prior to substantial deposition of aggregated tau and NFTs, and neurons that appeared to be dying exhibited no ultrastructural evidence of fibrillar tau (Andorfer et al., 2005).”

“showed that, while there was widespread neurodegeneration, the PHF-containing neurons appeared “healthy” in terms of nuclear morphology, suggesting that the polymerized protein was probably neuroprotective (105).”

“Selective Suppression of Soluble Tau Dimers by Curcumin in Aged hTauMice—AlthoughhTaumice develop age-dependent NFTs with neuronal hyperphosphorylated Tau accumulation by 12 months of age (22, 27), progression of pathophysiology beyond 17 months of age, specifically in relation to synaptic dysfunction or the presence…”

“Finally, the Ser422 epitope has not been analyzed in other available models similar to THY-­‐Tau22 such as the htau model [42] [43].”

“In addition, recent studies in transgenic mice producing wild-type human tau but no endogenous mouse tau have documented the formation of neurofibrillary tangles and neuronal cell death associated with altered CCEs (Andorfer et al., 2005).”

“…van Praag et al., 1999; Shors et al., 2002; Jin et al., 2004; Shors, 2004), particularly because disruption or overexpression of human protein tau affects the cell cycle, neuronal maturation, and axonal elongation (Takei et al., 2000; Dawson et al., 2001; Zhao et al., 2003; Andorfer et al., 2005).”

“In this model, expression of the normal tau protein is driven by the MAPT promoter and regulatory sequences (Andorfer et al., 2003, 2005).”

“Third, neuronal CCEs are observed in a variety of transgenic mouse models of AD [3, 8 ].”

“Like CELF1, hnRNP H regulates INSR splicing in the opposite direction compared to MBNL1/2 [97].”

“[108] Andorfer C, Acker CM, Kress Y et al.”

“Furthermore, evidence for a role of cell cycle-regulated genes in neurodegeneration has been obtained in mice transgenic for wild-type human tau (3) and in tau-expressing human neuroblastoma cells (Hoerndli et al, unpublished).”

“Over-expression of tau protein (a microtubule-associated protein), hyperphosphorylation and mutations are known to contribute to its aggregation [60–62].”

“Additionally, in animal models, disease phenotypes are not associated with NFT levels [7–15], including in mice overexpressing human tau (Htau mice) [16, 17].”

“…et al., 2010), axonogenesis (DiTella et al., 1994; Klein et al., 2002; Belkadi and LoPresti, 2008), interactions with the plasma membrane (Brandt et al., 1995; Lee et al., 1998; Maas et al., 2000), signal transduction (Lee et al., 2004; Ittner et al., 2010) and cell cycle (Andorfer et al., 2005).”

“Inflammation and cell death occur prior to, or independently, from the formation of NFTs in AD and in transgenic mouse models [9, 12, 13, 15, 31].”

“Our ongoing studies (unpublished) show that a cocktail containing both DHA and bioavailable curcumin can limit cognitive deficits and tau pathology in human tau mice beginning treatment at 14 months which is well after tau pathology and cognitive deficits had developed [190, 191].”

“PHF1 immunoreactivity, however, differed between adult and aged mice.”

“We have previously shown that tau-induced cell cycle reentry mediates neuronal apoptosis in the fly tauopathy model [18], a result that has been corroborated in rodent models model of tauopathy [23,24].”

“Interestingly, a recent transgenic mice study demonstrated that the overexpression of normal human tau protein induces neuronal apoptosis and cell cycle re-entry (Andorfer et al., 2005).”

“Notably, original reports on hTau mice suggested formation of mature tangles and neurodegeneration by 20 months of age [45, 62, 63].”

“…tangles: Histopathological and biochemical studies show that hippocampal CA1 pyramidal neurons of the AD brain bear intracellular NFTs, which have been modeled in mice that overexpress the human t protein (Ginsberg et al, 1999b; Trojanowski and Lee, 2005; Gotz, 2001; Andorfer et al, 2005).”

“This pathology is spatially distributed in relevant brain areas, such as the neocortex and hippocampus, with minimal brainstem and spinal cord involvement (30, 31).”

“Aged mice expressing nonmutant human tau in the absence of mouse tau (Htau mice) developed NFTs and extensive cell death in the piriform cortex and hippocampus (Andorfer et al., 2005).”

“Tau directly induces synaptic loss and dysfunction Tau can have toxic effects on the synapse resulting in density loss and synaptic dysfunction independent from Aβ [32].”

“Cell cycle re-entry has been observed in different neurodegenerative conditions, such as AD, PD, ALS or stroke (Ahn et al., 2008; Andorfer et al., 2005; Hoglinger et al., 2007; Lopes et al., 2009c; Neve and McPhie, 2006; Nguyen et al., 2003; Rashidian et al., 2005; Wen et al., 2005).”

“The first one uses the same 30mer peptide described above [102] in hTau/PS1 mice, which express all six wild-type isoforms of human tau on a mouse tau knockout background [34] plus human mutant (M146L) presenilin 1 (PS1) [105].”

“Similar results were obtained by immunizing mice that express all six human tau isoforms on an MAPT-/- background, the htau model (Andorfer et al., 2005), together with M146L mutant PS1 (Boutajangout et al.”

“These aged mice are further characterized by neuronal loss together with ventricle enlargement and reduced cortical thickness [56].”