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AAV-Tau Mediates Pyramidal Neurodegeneration by Cell-Cycle Re-Entry without Neurofibrillary Tangle Formation in Wild-Type Mice

Experimental Genetics Group, Department of Human Genetics, KULeuven-Campus, Leuven, Belgium.
PLoS ONE (Impact Factor: 3.23). 10/2009; 4(10):e7280. DOI: 10.1371/journal.pone.0007280
Source: PubMed

ABSTRACT In Alzheimer's disease tauopathy is considered secondary to amyloid, and the duality obscures their relation and the definition of their respective contributions.
Transgenic mouse models do not resolve this problem conclusively, i.e. the relative hierarchy of amyloid and tau pathology depends on the actual model and the genes expressed or inactivated. Here, we approached the problem in non-transgenic models by intracerebral injection of adeno-associated viral vectors to express protein tau or amyloid precursor protein in the hippocampus in vivo. AAV-APP mutant caused neuronal accumulation of amyloid peptides, and eventually amyloid plaques at 6 months post-injection, but with only marginal hippocampal cell-death. In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks. Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.
We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo. The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease.

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    • "It appears that cell cycle-positive neurons are committed to die, but they can survive in a compromised manner until they are hit by another detrimental factor (Zhu et al., 2004b, 2007). However, it has been reported that the intracerebral injection of adeno-associated viral particles containing mutations of tau or amyloid precursor protein (APP) leads to the ectopic expression of cell cycle-related genes (Jaworski et al., 2009), reinforcing the hypothesis of post-mitotic neurons forced to enter the cell cycle in AD. "
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    ABSTRACT: Cumulative evidence indicates that aberrant re-expression of many cell cycle-related proteins and inappropriate neuronal cell cycle control are critical events in Alzheimer's disease (AD) pathogenesis. Evidence of cell cycle activation in post-mitotic neurons has also been observed in murine models of AD, despite the fact that most of these mice do not show massive loss of neuronal bodies. Dysfunction of the cell cycle appears to affect cells other than neurons, as peripheral cells, such as lymphocytes and fibroblasts from patients with AD, show an altered response to mitogenic stimulation. We sought to determine whether cell cycle disturbances are present simultaneously in both brain and peripheral cells from the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD, in order to validate the use of peripheral cells from patients not only to study cell cycle abnormalities as a pathogenic feature of AD, but also as a means to test novel therapeutic approaches. By using cell cycle pathway-specific RT(2)Profiler™ PCR Arrays, we detected changes in a number of cell cycle-related genes in brain as well as in lymphocytes from APP/PS1 mice. Moreover, we found enhanced 5'-bromo-2'-deoxyuridine incorporation into DNA in lymphocytes from APP/PS1 mice, and increased expression of the cell proliferation marker proliferating cell nuclear antigen (PCNA), and the cyclin-dependent kinase (CDK) inhibitor Cdkn2a, as detected by immunohistochemistry in cortical neurons of the APP/PS1 mice. Taken together, the cell cycle-related changes in brain and blood cells reported here support the mitosis failure hypothesis in AD and validate the use of peripheral cells as surrogate tissue to study the molecular basis of AD pathogenesis.
    European Journal of Neuroscience 06/2012; 36(5):2609-18. DOI:10.1111/j.1460-9568.2012.08178.x · 3.67 Impact Factor
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    • "Direct injections of gene transfer vectors are a complimentary approach to express tau in amyloid mice or in rats (Klein et al., 2004; Jaworski et al., 2009) because the expression can be targeted to the most relevant brain regions, avoiding other parts of the CNS, as well as other tissues. Previous studies demonstrated widespread expression that was well contained within the hippocampus with an AAV9 GFP vector (Klein et al., 2008), without damage to cortex above the hippocampus along the needle track, which enables discrete study of the relationship of hippocampal tau pathology and memory-related behavior. "
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that involves cognitive decline and dementia. To model the hippocampal neurodegeneration and memory-related behavioral impairment that occurs in FTLD and other tau and TDP-43 proteinopathy diseases, we used an adeno-associated virus serotype 9 (AAV9) vector to induce bilateral expression of either microtubule-associated protein tau or transactive response DNA binding protein 43 kDa (TDP-43) in adult rat dorsal hippocampus. Human wild-type forms of tau or TDP-43 were expressed. The vectors/doses were designed for moderate expression levels within neurons. Rats were evaluated for acquisition and retention in the Morris water task over 12 weeks after gene transfer. Neither vector altered acquisition performance compared to controls. In measurements of retention, there was impairment in the TDP-43 group. Histological examination revealed specific loss of dentate gyrus granule cells and concomitant gliosis proximal to the injection site in the TDP-43 group, with shrinkage of the dorsal hippocampus. Despite specific tau pathology, the tau gene transfer surprisingly did not cause obvious neuronal loss or behavioral impairment. The data demonstrate that TDP-43 produced mild behavioral impairment and hippocampal neurodegeneration in rats, whereas tau did not. The models could be of value for studying mechanisms of FTLD and other diseases with tau and TDP-43 pathology in the hippocampus including Alzheimer's disease, with relevance to early stage mild impairment.
    Experimental Neurology 12/2011; 233(2):807-14. DOI:10.1016/j.expneurol.2011.12.002 · 4.62 Impact Factor
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    • "The data support this hypothesis only if it is valid in pathology and not physiologically. By extrapolation and comparison of data obtained in Tau.P301L and Tau.4R mice, we corroborate our thesis that, in pathology, wild-type Tau can be as effective as mutant Tau in causing dendritic problems and eventually neurodegeneration (Jaworski et al., 2009b, 2011). It is evident that wild-type protein Tau causes most tauopathies, including all cases of AD, the most frequent, albeit secondary tauopathy (Duyckaerts et al., 2009). "
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    ABSTRACT: Cognitive demise correlates with progressive brain tauopathy in dementing patients. Improved cognition of young Tau.P301L mice contrasts with dysfunction later in life and remains unexplained (Boekhoorn et al., 2006). To unravel early mechanisms, we composed a correlative time line of clinical symptoms, cognitive defects, and biochemical and pathological traits, including comprehensive analysis of dendritic spines in specified regions of the cortex and hippocampus of young and adult Tau.P301L mice. Remarkably, young Tau.P301L mice have not more, but more mature spines than wild-type mice, revealing the anatomical substrate for their improved cognition and LTP. Spine maturation remained high in the hippocampus of adult Tau.P301L mice. However, spines regressed in length paralleling impaired cognition and increased Tau phosphorylation (Terwel et al., 2005). Conversely, spine maturation was unaffected in adult Tau.4R mice, while spine density was increased and length reduced similar to Tau.P301L mice. To explain how protein Tau promoted spinogenesis, we analyzed hippocampal synaptosomes and dendritic spines for mouse and human Tau. While synaptosomes were positive for both mouse and human Tau, weak variable reaction in spines was observed only after fixation according to Bouin. Mouse Tau was absent from spines in wild-type mice, dissociating the pathological actions of Tau in transgenic mice by relocalization into dendrites and spines from the physiological actions of protein Tau in axons only. We conclude that mutant protein Tau modulates cognition and morphology of spines similarly and in both directions, with pathology later in life coinciding with increased phosphorylation and relocalization of Tau from axons to soma and processes.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2011; 31(49):18036-47. DOI:10.1523/JNEUROSCI.4859-11.2011 · 6.75 Impact Factor
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