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).”

“[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).”

“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].”

“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).”

“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].”

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

“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).”

“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].”