Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine

Abstract

In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. amyloid precursor protein ͉ transplantation ͉ immunohistochemistry ͉ neurogenesis ͉ Alzheimer's disease T ransplantation of neural stem cells (NSCs) to the developing brain and in animal models of neurodegeneration has demonstrated that migration and differentiation of these cells is regulated primarily by environmental cues (1-4). Pathological changes that occur in neurodegenerative disorders such as Alzheimer's disease (AD) may profoundly affect the brain microenvironment, which may in turn affect the fate of NSCs.The amyloid hypothesis, which postulates that ␤-amyloid (A␤) neurotoxicity plays a causative role in AD, has dominated much of AD research (5) and the absence of a lethal phenotype in amyloid-precursor protein (APP) knockout mice (6) has detracted attention from the physiological functions of APP. Several studies have shown that APP is involved in regulating neurite outgrowth, cell proliferation, neuronal migration, and differentiation (7-10). APP expression is also increased after brain injury, and increased levels are observed in apoptotic cells (11,12). Other studies report that A␤ inhibits NSC migration by increasing amyloid-associated cell death and by dysregulation of cellular calcium homeostasis (13,14). These findings suggest that not only A␤ but that also altered APP processing during the course of AD may have effects on stem cell biology.Previously, we showed that human NSCs (HNSCs) transplanted into aged rats differentiated into neural cells and could reverse age-associated cognitive impairment in these animals (3). This study demonstrated that the aged rat brain was capable of providing necessary environmental conditions for HNSCs to retain their multipotency and provided some evidence for the potential of stem cell replacement therapies to improve memory and cognitive deficits in AD. However, we recently found increased in vitro glial differentiation of HNSCs treated with high doses of secreted APP or transfected with wild-type APP (15). This finding suggests that stem cell replacement approaches would have reduced effectiveness in the AD brain, in which impaired APP metabolism would prevent or reduce neuronal differentiation of implanted cells. Therefore, we suggest that regulation of APP levels in the brain is necessary for implementing neuroplacement strategies.(Ϫ)-Phenserine is a recently developed cholinesterase inhibitor (ChEI) currently in clinical ...

Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis

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Typical and atypical stem cells in the brain, vitamin C effect and neuropathology

“…Despite this fundamental problem, researchers have injected stem cells or stem cell-derived neurons into various brain regions in AD mouse models with the hope of restoring brain function. While in some cases the transplanted animals showed no improvement, in others stem cell transplantation produced a substantial improvement in cognitive function (Blurton-Jones et al, 2009;Marutle et al, 2007). The mechanisms by which these stem cell transplants achieved behavioral improvements are however controversial; optimistic researchers have suggested that the improvement is due to the replacement of damaged neurons (Marutle et al, 2007).…”

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Transgenic Mice as a Model for Alzheimers Disease

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