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).”

“Transgenic mice expressing human tau develop tau pathology, aberrant cell cycle re-entry in neurons, lateonset neurodegeneration, spatial memory deficits, and synaptic dysfunction (Andorfer et al. 2003, 2005; Polydoro et al. 2009).”

“Lack of specific amyloid-beta(1-42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures.”

“Finally, a recent study utilizing the previously discussed htau transgenic mice [4] showed that neuron death in aged animals occurred in cells that did not have direct evidence of NFT formation.”

“Also, there are some works suggesting that tau toxicity could be dependent in an increase in its expression [31] or that the toxicity could be related to its fragmentation, yielding some specific peptides [32], or to its aggregation, but this point is also discussed, since some works suggest a protective role for larg…”

“Thus, Andorfer and colleagues used electron microscopy in their human tau (htau) mice, and reported that the presence of tau filaments did not correlate with the death of individual cells (Andorfer et al., 2005).”

“While the presence and density of NFTs correlates with cognitive decline in AD (2, 3), recent evidence indicates that NFTs are not neurotoxic, but that an earlier, abnormal tau species induces neurodegeneration (4, 5).”

“This mouse model displays early onset tau pathology and is generated by crossing hTau mice (Andorfer et al., 2005)withmice carrying theM146Lhumanpresenilin 1 (PS1)mutation (hTau/PS1) (Duff et al.”

“Some transgenic models expressing human wild type or mutant tau also exhibit cell death.(77,78) However, the cell death could be detected in areas not relevant to AD, such as spinal cord.”

“Similar cytoplasmic vacuolization in a human tau–expressing transgenic mouse model was interpreted to suggest a necrotic mechanism of decay, although other morphologic criteria implied more divergent pathways of cell death.(44) In our AAV-based model, dendrites and axoplasm of degenerating neurons appeared similarly d…”

“In fact, markers of cell death were not found in NFT bearing neurons in htau mice (Andorfer et al. 2005), indicating that cell death occurs independently of NFT.”

“Compared to the homozygous P301L mice, the htau mice have a slower progression of pathology that more closely resembles AD [4,5,70] and may be more amenable to clearance.”

“In AD, excessive DNA damage [22, 76, 104], altered DNA repair [49, 94], chromosomal abnormalities [98], senescence [123], lethal cell-cycle re-entry [2, 79, 121] and altered neuronal death [23, 24, 32, 68] have all been reported.”

“been inconclusive, with mixed features of apoptosis, necrosis and autophagy being detected through a variety of histological and biochemical strategies, which are difficult to extrapolate to the dynamic events that occur in vivo.(23) The overlap between apoptosis and necrosis pathways has been linked to insult exposur…”

“Htau mice develop age-dependent tau pathology in the hippocampus and cortex (Andorfer et al., 2003, 2005), with the resulting neurodegeneration preceded by deficits in object recognition and spatial memory (Polydoro et al., 2009).”

“…the somato-dendritic compartment were achieved as early as 2 months of age (Andorfer et al. 2003), resulting in neuronal loss together with ventricle enlargement and reduced cortical thickness (Andorfer 2005), memory deficits and perturbed long-term potentiation at older age (Polydoro et al. 2009).”

“Hyperphosphorylation of tau may also induce abnormal, incomplete neuronal cell cycle re-entry (Andorfer et al., 2005), but the role of inflammatory cytokines in the re-entry effort is unknown.”

“Andorfer et al. (2005) observed a disparity between tangle burden and neuronal mortality in their investigation and similar illness models.”

“There is an apparent dissociation between the presence of an NFT and neuron death as demonstrated by Andorfer et al. (2005) who found that in htau mice (which overexpress wild-type human tau), substantial neuronal death precedes NFT formation, and dying neurons lack evidence of fibrillar tau…”

“Although the exact identity of the fragment is unknown, expression of an approximate recombinant version, tau [45-230], can lead to apoptosis in cell culture [118].”

“Moreover, it has been suggested that oligomeric forms of tau might be instrumental in neuronal death (15).”

“Other data demonstrated that neuronal death is coincided with neurofibrillary tangles [154], which are composed by hyperphosphorylated aggregates of the microtubuleassociated tau protein in some neurodegenerative disorders known as tauopathies, of which Alzheimer’s disease is one of the most notable.”

“On the other hand, Andorfer et al (68) showed that in human tau transgenic mice, PHF-containing neurons seem Bhealthy[ in terms of nuclear morphology, but speculations that the polymerization of hyperphosphorylated tau into fibrils is neuroprotective conflict with the neuronal nucleus misplacement and deformation and…”

“zone (SVZ) (Andorfer et al. 2005).”

“As in humans, these mice accumulate hyperphosphorylated tau over time and develop NFTs in regions of the brain that are affected in the human disease (Andorfer et al. 2003, 2005).”

“Similar to the important role of various soluble oligomeric Aβ species in AD, different soluble oligomeric forms of tau may also play a critical role in AD, also causing neuronal loss and cognitive dysfunction [19, 54, 55].”

“Filamentous tau aggregates are present in brains of the DM tg mice EM studies of the sarcosyl insoluble fractions in DM tg mice of about 10 months of age revealed the presence of tau filaments stained with Tau13 as well as with CP13, indicating the aggregation of the human DM tau in a filamentous form, with evidence f…”

“The htau mice examined in this study were relatively young, given that the on onset of neurodegeneration in these mice occurs at approximately 14 months of age (Andorfer et al., 2005).”

“To generate a more ideal model for AD, other researchers have used a single wild-type human tau to generate a transgenic model; however, most of these models did not develop NFTs, with the exception of two models: one expressing ON3R wild-type tau with a few NFTs in aged animals [116] and another with abundant NFTs th…”

“Expression of cell cycle-related proteins fueled the hypothesis that post-mitotic neurons attempting to reactivate cell-cycling contribute to neurodegeneration in AD”

“In both the rTg4510 and hTau lines, neuronal tau aggregates form, but neurons without aggregates are more susceptible to death.(75,76) Furthermore, in vivo imaging in rTg4510 mice suggests that tangle formation reduces the likelihood of cell death.”

“We have previously shown that tau-induced cell cycle reentry mediates neuronal apoptosis in the fly tauopathy model [20], a result that has been corroborated in rodent models model of tauopathy [32,33].”

“This is consistent with the recently achieved consensus that pathological structures like NFTs are not involved in neuronal death (Andorfer et al., 2005; Santacruz et al., 2005).”

“loss in our AAV-based model is in agreement with reports in other tau models, including the rTg4510 and humanized tau mousemodels (50,51), although future studieswill need to assess whether neuronal loss is observed in the AAV1-Tau model beyond 6 months of age.”

“[10] 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 polymerized protein was probably neuroprotective [10].”

“However, removing endogenous mouse tau from these transgenic mice led to spatial memory deficits, perturbed LTP, as well as significant neuronal loss, ventricle enlargement, and reduced cortical thickness (Ando et al., 2011; Andorfer et al., 2005; Polydoro, Acker, Duff, Castillo & Davies, 2009).”

“(2007) 103, 2256–2267 2007 The Authors with age and they develop PHF-containing NFT-like inclusions (Andorfer et al. 2003, 2005).”

“Our finding is consistent with those reported in a mouse model expressing wild type tau where it was found that although PCNA was detected, it did not co-localize with tau pathology [19].”

“…assembly of tubulin (Amniai et al., 2009), disrupting axonal transport (Cuchillo-Ibanez et al., 2008), causing reentry of neurons into the cell cycle (Andorfer et al., 2005), and possibly leading to further abnormal tau processing, for example, truncation by proteases (Rametti et al., 2004) or…”

“occurs after tau hyperphosphorylation in the mice around 9 months of age (Andorfer et al. 2005).”

“Such functions include interactions with the plasma membrane [4-8], signal transduction (via the N terminal projection domain of tau) [7] and diverse developmental functions including the cell cycle [8], tissue patterning [9] neuronal polarization and axon identity [9-11] and various aspects of axonogenesis [12-16].”

“At this location, it is postulated that tau protein might play a relevant role in DNA protection [16] and in regulating the cell cycle [17].”

“For instance, cell death and synaptic lesions occur independently of NFT formation in htau mice expressing nonmutant human tau [13,14].”

“Surprisingly, hyperphosphorylation of tau in hTau transgenic mice expressing all six isoforms of human tau (Andorfer et al., 2003, 2005), led to the specific dissociation of tau from the MTs in old mice.”

“Studies in other tauopathy models have also called into question the role played by hyperphosphorylation in the chain of events leading to degeneration; recent fly model studies (159) have suggested that hyperphosphorylation can be neuroprotective by blocking other aspects of tau toxicity, such as apoptotic changes as…”

“This notion leave open the possibilities that tau tangles further contribute to the pathology or function protectively or do both by transition from an initially protective reaction to a pathological process [101, 113, 122].”

“transgenic mouse models of tauopathies have shown that cell death and cognitive deficits during tau aggregation are uncorrelated with fibril load, and hence, some early species is responsible for toxicity.(82,83) Future studies will hence address the possibility that fibril heterogeneity as a result of this newly disc…”

“Recent studies have linked early modifications in the structures of soluble tau proteins, particularly their phosphorylation, to neurodegeneration [240, 241].”

“Moreover, protein Tau but not NFT appeared involved in neuronal death in transgenic mice and AD patients [44, 45].”

“number to account for the dramatic loss in neurons observed in this model [88].”

“The present studies sought to examine the effects of pathological MAPT on adult neurogenesis in the genomic-based hTau mouse model of tauopathy (Andorfer et al., 2003, 2005; Polydoro et al., 2009).”

“It has been suggested that as well as an increase in the amount of tau (Andorfer et al., 2005), structural changes to this protein, modifications by phosphorylation, or its aggregation could produce toxic effects in cells (Avila et al., 2004; Duff and Planel, 2005; Bretteville and Planel, 2008;…”

“Tau hyperphosphorylation may also induce abnormal, incomplete cell cycle re-entry (Andorfer et al. 2005).”

“On the other hand, only the overexpression of wild-type human tau in a mouse is sufficient to cause tau phosphorylation, aggregation, and neural toxicity [43].”

“A number of studies have demonstrated DNA replication and cell cycle activation within postmitotic neurons in tauopathies, including Alzheimer’s disease and related disorders (Andorfer et al., 2005; Herrup & Yang, 2007).”

“This pathology is very similar to that caused by misexpression of either mutant or wild-type tau in other models [31,32], emphasizing that multiple pathways affecting tau expression levels, dephosphorylation [33], and phosphorylation may Neurobiological aspects of Alzheimer’s disease”

“Correlative data have begun to accumulate in animal models of pathology, including APP-transgenic mouse models of AD [11-12], aged mice expressing non-mutant human tau [13], and Drosophila models of tauopathies [14].”

“animal models of tauopathy and in postmortem human brains.(85,86,128,129,135) For example, quantitative analysis of hippocampal tissue sections double labeled for AO and TS demonstrates approximately 80% of TS-positive NFTs are AO-positive.”

“Noteworthy, introduction of the entire human MAPT gene in the mouse genome led to expression of all six human tau isoforms in neurons [53,54].”

“Recent research has shown that the most toxic form of Tau is not NFTs themselves, but rather the smaller aggregates, called Tau oligomers, which are likely to initiate neurodegeneration in tauopathies (Andorfer et al., 2005; Cowan and Mudher, 2013; Fox et al., 2011; Ishihara et al., 1999; Ishihara et al., 2001; Le Cor…”

“4A), adult htau mice express all human tau isoforms, with an excess of 3R tau over 4R tau [(14, 15) and Fig.”

“Studies have shown synaptic dysfunction in transgenic tau mice despite their inefficiency to unravel whether or not functional deficits precede the manifestation of NFTs [50, 60, 61].”

“dying neurons often do not contain tangles (G omez-Isla et al., 1997; Andorfer et al., 2005; Spires et al., 2006).”

“Over the years, other experimental studies [57, 80], correlative evidence from post-mortem studies (Table 1), and the fact that cell cycle reactivation often accompanies Aβ-, and taumediated cell death have been supportive of this phenomenon [1, 22, 32, 43, 47].”