Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease

Ebert, Allison D.; Beres, Amy; Barber, Amelia E.; Svendsen, Clive N.

doi:10.1016/j.expneurol.2007.09.022

Cited by 138 publications

(110 citation statements)

References 51 publications

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“…The strategy of using stem cells as a drug delivery system for brain tumors has been applied in the rodent for >10 years [34]. Additional studies showed that the delivery of glial cell line-derived neurotrophic factor through engineered human neural progenitor cells improved neurons survival and function in the rodent models of Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis [35][36][37][38]. Likewise, transplantation of MGE cells into the epileptic cortex has been proposed as a cell-based therapy for medically intractable epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

et al. 2011

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Interneuron progenitors from the embryonic medial ganglionic eminence (MGE) can migrate, differentiate, and enhance local inhibition after transplantation into the postnatal cortex. Whether grafted MGE cells can reduce ictal activity in adult neocortex is unknown. We transplanted live MGE or killed cells (control) from pan green fluorescent protein expressing mice into adult mouse sensorimotor cortex. One week, 2 and 1/2 weeks, or 6 to 8 weeks after transplant, acute focal ictal epileptiform discharges were induced by injection of 4-aminopyridine (4-AP) 2 mm away from the site of transplantation. The local field potential of the events was recorded with 2 electrodes, 1 located in the 4-AP focus and the other 1 in the transplantation site. In all control groups and in the 1-week live cell transplant, 4-AP ictal discharges revealed no attenuation in power and duration from the onset site to the site of transplantation. However, 2.5 or 6~8 weeks after MGE transplants, there was a dramatic decrease in local field potential power at the MGE transplanted site with little decrease in ictal duration. Surprisingly, there was no relationship between grafted cell distribution or density and the degree of attenuation. As remarkably low graft densities still significantly reduced discharge power, these data provide further support for the therapeutic potential of interneuron precursor transplants in the treatment of neocortical epilepsy.

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Section: Discussionmentioning

confidence: 99%

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

et al. 2011

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“…However, studies have begun to examine stem cell-based therapies as a novel strategy to treat disorders such as Parkinson disease, ischemia, and spinal cord injury (1)(2)(3). Notably, each of these disorders primarily affects a single neuronal subtype and/or a restricted anatomical region.…”

mentioning

confidence: 99%

Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease

Blurton‐Jones

Kitazawa²,

Martínez-Coria³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

757

583

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Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Aß plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Aß or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brainderived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.beta-amyloid ͉ neurotrophin ͉ synapse ͉ tau ͉ memory

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“…With the identification of AF4 as a negative regulator of Igf-1 gene expression in the cerebellum, and possibly in other regions of the brain, this study opens new avenues of research into the manipulation of the IGF-1 signaling pathway for the treatment of a whole range of human degenerative diseases (Ebert et al, 2008;Palazzolo et al, 2009), in particular for cerebellar ataxia (Fernandez et al, 2005;Zhong et al, 2005;Vig et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

AF4 Is a Critical Regulator of the IGF-1 Signaling Pathway during Purkinje Cell Development

Bitoun¹,

Finelli²,

Oliver³

et al. 2009

J. Neurosci.

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Deregulation of the insulin-like growth factor 1 (IGF-1) signaling pathway is a recurrent finding in mouse models and human patients with cerebellar ataxia and thus represents a common pathological cascade in neuronal cell death that may be targeted for therapy. We have previously identified a point mutation in AF4, a transcription cofactor of RNA polymerase II elongation and chromatin remodeling, that causes progressive and highly specific Purkinje cell (PC) death in the ataxic mouse mutant robotic, leading to the accumulation of AF4 in PCs. Here we confirm that the spatiotemporal pattern of PC degeneration in the robotic cerebellum correlates with the specific profile of AF4 upregulation. To identify the underlying molecular pathways, we performed microarray gene expression analysis of PCs obtained by laser capture microdissection (LCM) at the onset of degeneration. Igf-1 was significantly downregulated in robotic PCs compared with wild-type controls before and throughout the degenerative process. Consistently, we observed a decrease in the activation of downstream signaling molecules including type 1 IGF receptor (IGF-1R) and the extracellular signal-regulated kinase (ERK) 1 and ERK2. Chromatin immunoprecipitation confirmed that Igf-1 is a direct and the first validated target of the AF4 transcriptional regulatory complex, and treatment of presymptomatic robotic mice with IGF-1 indeed markedly delayed the progression of PC death. This study demonstrates that small changes in the levels of a single transcriptional cofactor can deleteriously affect normal cerebellum function and opens new avenues of research for the manipulation of the IGF-1 pathway in the treatment of cerebellar ataxia in humans.

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Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease

Cited by 138 publications

References 51 publications

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease

AF4 Is a Critical Regulator of the IGF-1 Signaling Pathway during Purkinje Cell Development

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