Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy
Tau protein in a hyperphosphorylated state makes up the intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease and cases of frontotemporal dementia. Mutations in Tau cause familial forms of frontotemporal dementia, establishing that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. Transgenic mice expressing human mutant tau in neurons exhibit the essential features of tauopathies, including neurodegeneration and abundant filaments composed of hyperphosphorylated tau. Here we show that a previously described mouse line transgenic for human P301S tau exhibits an age-related, layer-specific loss of superficial cortical neurons, similar to what has been observed in human frontotemporal dementias. We also show that focal neural precursor cell implantation, resulting in glial cell differentiation, leads to the sustained rescue of cortical neurons. Together with evidence indicating that astrocyte transplantation may be neuroprotective, our findings suggest a beneficial role for glial cell-based repair in neurodegenerative diseases.
Available from: biohorizons.oxfordjournals.org
- "Work has also been done in other mouse models that try to recapitulate some of the salient features of Alzheimer's. Hampton et al. (2010) used a mouse model of human tauopathy P301S (). This mouse has an age-related build-up of hyperphosphorylated human tau in the brain. "
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ABSTRACT: Alzheimer's disease is a growing concern with no satisfactory current treatment solution. Contemporary stem cell research
offers a new arena for development in this field. Transplantation of stem cells into the damaged brain brings hope of repair
to damaged neurons. This appears to operate via a ‘bystander effect’ whereby neurotrophins secreted by the cells act as a
neuroprotectant, rather than a cell replacement mechanism as some have postulated. Such treatments can slow or even reverse
cognitive decline. Research into neural stem cell transplantation has shown reversal of cognitive decline in animal models
of disease via the mechanism of brain-derived neurotrophic factor secretion. Studies using nerve growth factor secreting stem
cells have showed promising results with cognitive decline reversed in animal models of the disease. A Phase 1 clinical trial
also showed promising reversal of cognitive decline in human subjects using transplantation of nerve growth factor secreting
fibroblasts. Mesenchymal stem cells have also shown promise, and results from human trials are awaited. Induced pluripotent
stem cells have provided a successful model of human disease in vitro. Although early results from transplant studies are encouraging, a lot more research will be needed before these preliminary
advances can be translated to therapies with a strong evidence base to be used in practice.
Available from: Carmel O'Brien
- "shRNA-mediated silencing of NSC-derived BDNF could abrogate this protective effect . Similarly, in a model of neurofibrillary tangle formation in which expression of human mutant tau leads to the aged-related loss of cortical neurons, delivery of neural precursor cells into the cortical gray matter led to increased glial-derived neurotrophic factor levels and protection of cortical neurons . In addition to their neuroprotective effect, the anti-inflammatory activity of most neural cell types may also influence AD pathology through modulation of the microglial innate immune response . "
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ABSTRACT: The advent of human induced pluripotent stem cells (hiPSCs), reprogrammed in vitro from both healthy and disease-state human somatic cells, has triggered an enormous global research effort to realize personalized regenerative medicine for numerous degenerative conditions. hiPSCs have been generated from cells of many tissue types and can be differentiated in vitro to most somatic lineages, not only for the establishment of disease models that can be utilized as novel drug screening platforms and to study the molecular and cellular processes leading to degeneration, but also for the in vivo cell-based repair or modulation of a patient's disease profile. hiPSCs derived from patients with the neurodegenerative diseases amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and multiple sclerosis have been successfully differentiated in vitro into disease-relevant cell types, including motor neurons, dopaminergic neurons and oligodendrocytes. However, the generation of functional iPSC-derived neural cells that are capable of engraftment in humans and the identification of robust disease phenotypes for modeling neurodegeneration still require a number of key challenges to be addressed. Here, we discuss these challenges and summarize recent progress towards the application of iPSC technology for these four common neurodegenerative diseases.
Available from: Mathew Blurton-Jones
- "Biologic-based approaches, such as stem cell transplantation, are therefore receiving increasing attention. Recently, we and others showed that neural stem cell (NSC) transplantation markedly improves cognitive function, synaptic connectivity and neuronal survival in models of AD and tauopathy [3,4]. Many of these effects appear to be mediated by stem cell-derived neurotrophins or other neuroprotective activities. "
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Short-term neural stem cell (NSC) transplantation improves cognition in Alzheimer’s disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, this approach has no effect on the underlying beta-amyloid (Aβ) and neurofibrillary tangle pathology. Long term efficacy of cell based approaches may therefore require combinatorial approaches.
To begin to examine this question we genetically-modified NSCs to stably express and secrete the Aβ-degrading enzyme, neprilysin (sNEP). Next, we studied the effects of sNEP expression in vitro by quantifying Aβ-degrading activity, NSC multipotency markers, and Aβ-induced toxicity. To determine whether sNEP-expressing NSCs can also modulate AD-pathogenesis in vivo, control-modified and sNEP-NSCs were transplanted unilaterally into the hippocampus of two independent and well characterized transgenic models of AD: 3xTg-AD and Thy1-APP mice. After three months, stem cell engraftment, neprilysin expression, and AD pathology were examined.
Our findings reveal that stem cell-mediated delivery of NEP provides marked and significant reductions in Aβ pathology and increases synaptic density in both 3xTg-AD and Thy1-APP transgenic mice. Remarkably, Aβ plaque loads are reduced not only in the hippocampus and subiculum adjacent to engrafted NSCs, but also within the amygdala and medial septum, areas that receive afferent projections from the engrafted region.
Taken together, our data suggest that genetically-modified NSCs could provide a powerful combinatorial approach to not only enhance synaptic plasticity but to also target and modify underlying Alzheimer’s disease pathology.
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