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).”

“A transgenic mouse line of WT human tau overexpression generated by the Davies laboratory 42 displayed tau hyperphosphorylation and fi lamentous aggregation, neuronal cell death 43 , and synaptic and cognitive dysfunction 44 .”

“Later in life (>15 months), thioflavine-S-positive neurofibrillary tangles (NFTs) have also been reported [22,26].”

“Cg- (GFP)Klt Tg(MAPT)8cPdav/J) in a C57BL/6 background (Jackson laboratories; reference: RRID:IMSR_JAX:005491; Bar Harbor, ME, USA) [31,32].”

“In fact, there is some evidence suggesting that NFT might be protective indeed, as tangle-bearing neurons seem to survive for long periods of time (Andorfer et al., 2005; de Calignon et al., 2009; Morsch et al., 1999).”

“The tauopathy in the Htau model is somewhat slow to develop; mice older than 15 months of age developed tauopathy, DNA fragmentation and a quantitative loss of neurons [58,59].”

“Even more, the cells that accumulate filamentous tau appear “healthy” in terms of nuclear morphology, suggesting that the polymerized protein is protective for the neurons [7].”

“It was observed in transgenic mice expressing nonmutant human tau isoforms that themechanismof neurodegeneration involved reexpression of cell cycle proteins and DNA synthesis, indicating that nonmutant tau pathology and neurodegenerationmay be linked via abnormal, incomplete cell cycle reentry (Andorfer et al. 2005;…”

“Other controversial observations suggest that neuronal death coincides with the formation of neurofibrillary tangles, which are composed of hyperphosphorylated tau protein (Andorfer et al., 2005).”

“For normal human tau-expressing transgenic mice, increased tau phosphorylation occurred, along with insoluble tau being found in the brains of aged mice [157].”

“Given the link between aberrant cell cycle activation in postmitotic neurons and neurodegeneration 84 – 86 , as well as the reduction of adult hippocampal neurogenesis in cognitive decline 87,88 , it is possible that the defective mitotic function of tau in neurons could have broader implications…”

“WT tau, unlike its mutant counterparts associated with FTDP-17, is generally resistant to aggregation under physiological conditions (Andorfer et al., 2005; Ferrari et al., 2003; Götz et al., 1995).”

“When levels of intracellular tau protein increase, they may be secreted into the extracellular space (Sim ´ on et al., 2012a) and exert toxic effects on cells (Andorfer et al., 2005; G ´ omez-Ramos et al., 2008).”

“In Figure 2”

“The 8c mice express a tau transgene, derived from a human PAC driven by the tau promoter, and produce all human tau isoforms (Andorfer et al., 2005).”

“Cell death and synaptic lesions occurred independently of NFT formation (h-tau mice) expressing non-mutant human tau (Andorfer et al. 2005, Polydoro et al. 2009); hippocampal synapse loss, impaired synaptic function and microgliosis precede the formation of NFT in the P301S mutant human tau…”

“Transgenic mice expressing Human Tau on a C57BL/6 and null murine tau background (hTau generated as previously described [25, 26]) were purchased from Jackson Laboratories (Stock # 005491), Bar Harbor, Maine.”

“Given the link between aberrant cell cycle activation in postmitotic neurons and neurodegeneration ( 76 – 78 ), as well as the reduction of adult hippocampal neurogenesis in cognitive decline ( 79 , 80 ), it is plausible that defective tau function during cell division could have broader…”

“The animals displayed hyperphosphorylated tau and NFT formation as well as changes in neuronal morphology and a decrease in cortical thickness due to extensive cell death (Andorfer et al., 2005; Andorfer et al., 2003).”

“Ces résultats ont été appuyés par les travaux d’Andorfer et ses collaborateurs qui ont observés dans un modèle murin sur-exprimant la protéine Tau humaine mutée (P310L, mutation responsable de certain type de démence fronto-temporale), une mort neuronale indépendante des DNF (Andorfer et al., 2005).”

“Furthermore, the observed dissociation between tau burden and toxicity aligns with previous studies showing functional preservation despite persistent pathology [2, 3, 10, 38, 42, 44, 46].”

“It drives abnormal neuronal cell-cycle re-entry, 103–107 enhances A β plaque formation 32,108 and promotes Tau hyperphosphorylation 109,110 through both transcriptional regulation and PTMs.”

“In some mouse models, such as in one expressing human tau but not mouse tau, cell death and dysfunction precede the detection of sarkosyl-insoluble tau filaments and thioflavin-S positive tau inclusions, implicating soluble tau species (Andorfer et al., 2005).”

“Davies and colleagues developed a genomic mouse model of human MAPT pathology (termed hTau) by expressing the entire wild-type human MAPT gene in mice lacking the endogenous Mapt gene [9, 10].”

“Increasing evidence have revealed that aberrant cell cycle re-entry leads to neuronal death [8,32,37-64], and cell cycle inhibition via blocking SFKs can protect neurons from death post-ICH [8].”

“…2009), or il semble aujourd’hui que ces espèces constituent plutôt un réservoir de protéines tau à la toxicité modérée (Morsch et al., 1999 ; Andorfer et al., 2005 ; Spires et al., 2006), et que les espèces oligomériques de tau, plus solubles, soient à l’origine des effets toxiques de tau…”

“As seen in mice bearing the non-mutant human tau gene, dying neurons did not contain NFT, while those bearing NFT maintained robust nuclear morphology (Andorfer et al. 2005).”

“Over the last 10 years, the researchers interested in the field of neurodegenerative tauopathies made important findings, mostly thanks to development of transgenic animals expressing wild type, mutated or tau protein corresponding to the pathological truncation seen in AD (Probst et al. 2000; Gotz et al. 2001; Tanemu…”

“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.”

“Similarly, a cell culture model expressing P301L mutant tau was found to up-regulate numerous genes associated with cell cycle re-entry upon exposure to Aβ including cdk1, cdk4, and PCNA (Hoerndli et al., 2007).”

“In addition, expression of wild-type tau could induce cell death independently of NFT formation, possibly mediated by cell-cycle re-entry (Andorfer et al. 2005).”