sAPPalpha enhances the transdifferentiation of adult bone marrow progenitor cells to neuronal phenotypes.

Molecular Neuropathology Laboratory, Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
Current Alzheimer Research (Impact Factor: 3.89). 03/2006; 3(1):63-70.
Source: PubMed


The remediation of neurodegeneration and cognitive decline in Alzheimer's Disease (AD) remains a challenge to basic scientists and clinicians. It has been suggested that adult bone marrow stem cells can transdifferentiate into different neuronal phenotypes. Here we demonstrate that the alpha-secretase-cleaved fragment of the amyloid precursor protein (sAPPalpha), a potent neurotrophic factor, potentiates the nerve growth factor (NGF)/retinoic acid (RA) induced transdifferentiation of bone marrow-derived adult progenitor cells (MAPCs) into neural progenitor cells and, more specifically, enhances their terminal differentiation into a cholinergic-like neuronal phenotype. The addition of sAPPalpha to NGF/RA-stimulated MAPCs resulted in their conversion to neuronal-like cells as evidenced by the extension of neurites and the appearance of immature synaptic complexes. MAPCs differentiated in the presence of sAPPalpha and NGF/RA exhibited a 40% to as much as 75% increase in neuronal proteins including NeuN, beta-tubulin III, NFM, and synaptophysin, compared to MAPCs differentiated by NGF/RA alone. This process was accompanied by an increase in the levels of choline acetyltransferase, a marker of cholinergic neurons, compared to those of GABAergic and dopaminergic neuronal subtypes. MAPCs immunopositive for sAPPalpha were identified within the septohippocampal system of transgenic PS/APP mice injected intravenously with sAPPalpha-transfected MAPCs and found in close proximity to the cerebral vasculature. Given that in AD cholinergic neurons are severely vulnerable to neurodegeneration and that the levels of sAPPalpha are significantly reduced, these findings suggest the combined use of sAPPalpha and MAPCs offers a new and potentially powerful therapeutic strategy for AD treatment.

Download full-text


Available from: Wen-Fu T. Lai, May 27, 2014
  • Source
    • "Previous studies have reported that overexpression of the retinoblastoma family gene, RB, triggers cholinergic phenotypes in hMSCs [63]. In addition, one study reported that secreted amyloid precursor protein-α (sAPPα) promoted cholinergic differentiation in mouse MSCs [64]. Our study demonstrated that Wnt7a promotes cholinergic differentiation in hMSCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wnts were previously shown to regulate the neurogenesis of neural stem or progenitor cells. Here, we explored the underlying molecular mechanisms through which Wnt signaling regulates neurotrophins (NTs) in the NT-induced neuronal differentiation of human mesenchymal stem cells (hMSCs). NTs can increase the expression of Wnt1 and Wnt7a in hMSCs. However, only Wnt7a enables the expression of synapsin-1, a synaptic marker in mature neurons, to be induced and triggers the formation of cholinergic and dopaminergic neurons. Human recombinant (hr)Wnt7a and general neuron makers were positively correlated in a dose- and time-dependent manner. In addition, the expression of synaptic markers and neurites was induced by Wnt7a and lithium, a glycogen synthase kinase-3β inhibitor, in the NT-induced hMSCs via the canonical/β-catenin pathway, but was inhibited by Wnt inhibitors and frizzled-5 (Frz5) blocking antibodies. In addition, hrWnt7a triggered the formation of cholinergic and dopaminergic neurons via the non-canonical/c-jun N-terminal kinase (JNK) pathway, and the formation of these neurons was inhibited by a JNK inhibitor and Frz9 blocking antibodies. In conclusion, hrWnt7a enhances the synthesis of synapse and facilitates neuronal differentiation in hMSCS through various Frz receptors. These mechanisms may be employed widely in the transdifferentiation of other adult stem cells.
    Full-text · Article · Aug 2014 · PLoS ONE
  • Source
    • "In human embryonic stem cells (hESCs), the overexpression of APP or its soluble forms causes rapid and robust differentiation toward a neural fate (Freude et al., 2011). Furthermore, in adult bone marrow progenitor cells, sAPPα enhances transdifferentiation to neuronal phenotypes (Chen et al., 2006). The role of Aβ in the fate determination of NPCs has also been described, as treatment of SVZ-derived NPCs with the Aβ 42 isoform pushes differentiation toward a neuronal fate (Heo et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interest in the amyloid precursor protein (APP) has increased in recent years due to its involvement in Alzheimer's disease. Since its molecular cloning, significant genetic and biochemical work has focused on the role of APP in the pathogenesis of this disease. Thus far, however, these studies have failed to deliver successful therapies. This suggests that understanding the basic biology of APP and its physiological role during development might be a crucial missing link for a better comprehension of Alzheimer's disease. Here, we present an overview of some of the key studies performed in various model organisms that have revealed roles for APP at different stages of neuronal development.
    Preview · Article · Jul 2014 · Development
  • Source
    • "The SCI method in this study followed previously published protocols that are widely used [35] [36]. The BBB score has been well defined to evaluate the locomotive recovery after SCI since BBB developed it in 1994 [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent advanced studies have demonstrated that cytokines and extracellular matrix (ECM) could trigger various types of neural differentiation. However, the efficacy of differentiation, and in vivo transplantation has not yet thoroughly been investigated. Highlight the current understanding of effects of ECM on neural differentiation of human bone marrow-derived progenitor cells (MPCs), regarding state-of-the-art cure for the acute spinal cord-injured animal, and explore future treatments aimed at neural repair. Study Design/Setting: A selective overview of the literature pertaining to the neural differentiation of MSCs and experimental animals aimed at improved the repair of spinal cord injury. ECM proteins, TN-C, tenascin-restrictin (TN-R), and chondroitin sulfate (CS), with the cytokines, NGF/BDNF/RA (NBR), were incorporated to induce transdifferentiation of hMPCs. Cells were treated with NBR for 7 days, and then TN-C, TN-R, or CS was added for 2 days. The medium was changed every 2 days. Twenty-four animals were randomly assigned to four groups with 6 animals in each group: 1 experimental and 3 control. Animals received two injections of vehicle, MPCs, NBR induced-MPCs, or NBR/ TN-C-induced into the lesion sites after spinal cord injury. Functional assessment was measured using the Basso, Beattie, and Bresnahan Locomotor Rating Score. Data were analyzed using ANOVA followed by SNK post-hoc tests. Results showed that MPCs with the transdifferentiation of hMPCs to neurons were associated with increased mRNA expression of neuronal markers including nestin, microtubule-associated protein (MAP)2, glial fibrillary acidic protein (GFAP), βIII tubulin, and NGF. Greater amounts of neuronal morphology appeared in cultures incorporating with TN-C and TN-R than those with CS. The addition of TN-C enhanced mRNA expressions of MAP2, βIII tubulin, and NGF, while TN-R did not significantly change. Conversely, CS exposure decreased MAP2, βIII tubulin, and NGF expressions. The TN-C-treated MSCs significantly and functionally repaired spinal cord injury-induced rats at Day 42. Present results indicate that ECM components, such as tenascins and CS in addition to cytokines, may play functional roles in regulating neurogenesis by hMPCs. These findings suggest that the combined use of TN-C, NBR, and hMPCs offers a new feasible method for nerve repair.
    Full-text · Article · Apr 2014 · The spine journal: official journal of the North American Spine Society
Show more