ABSTRACT
The amyloid precursor protein (APP) has been mainly studied in its role in the production of amyloid ß peptides (Aß), because Aß deposition is a hallmark of Alzheimer's disease. Although several studies suggest APP has physiological functions, it is still controversial. We previously reported that APP increased glial differentiation of neural progenitor cells (NPCs). In the current study, NPCs transplanted into APP23 transgenic mice primarily differentiated into glial cells. In vitro treatment with secreted APP (sAPP) dose-dependently increased glial fibrillary acidic protein (GFAP) immuno-positive cells in NPCs and over expression of APP caused most NPCs to differentiate into GFAP immuno-positive cells. Treatment with sAPP also dose-dependently increased expression levels of GFAP in NT-2/D1 cells along with the generation of Notch intracellular domain (NICD) and expression of Hairy and enhancer of split 1 (Hes1). Treatment with γ-secretase inhibitor suppressed the generation of NICD and reduced Hes1 and GFAP expressions. Treatment with the N-terminal domain of APP (APP 1-205) was enough to induce up regulation of GFAP and Hes1 expressions, and application of 22 C11 antibodies recognizing N-terminal APP suppressed these changes by sAPP. These results indicate APP induces glial differentiation of NPCs through Notch signaling.
Subject(s)
Amyloid beta-Protein Precursor/metabolism , Cell Differentiation , Neuroglia/cytology , Neuroglia/metabolism , Receptors, Notch/metabolism , Signal Transduction , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor/chemistry , Amyloid beta-Protein Precursor/genetics , Animals , Cell Line , Gene Expression Regulation , Glial Fibrillary Acidic Protein/genetics , Humans , Male , Mice , Mice, Transgenic , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/metabolism , Protein Structure, Tertiary , Stem Cells/cytologyABSTRACT
Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising.
Subject(s)
Cell- and Tissue-Based Therapy/methods , Neurodegenerative Diseases/therapy , Stem Cell Transplantation , Alzheimer Disease/therapy , Amyotrophic Lateral Sclerosis/therapy , Humans , Multiple Sclerosis/therapy , Parkinson Disease/therapy , Stem Cells/metabolismABSTRACT
Although amyloid precursor protein (APP) due to the cytotoxicity of Aß peptides, has been intensively studied, the physiological role of APP still remains wrapped up in veil. In this article, we propose that α-cleaved ectodomain of APP (sAPPα) stimulates the IL-6/gp130 signaling pathway for induction of gliogenesis within neural progenitor cells (NPCs). In our previous study, a high dose of APP differentiated NPCs into glial fibrillary acidic protein (GFAP) positive cells. In order to elucidate the mechanism of APP-induced glial differentiation, we examined the effects of sAPPα on the IL-6/gp130 signaling pathway. Application of sAPPα promoted mRNA expression of gp130, ciliary neurotrophic factor (CNTF), and Janus kinase 1 (JAK1). sAPPα stimulated the glial differentiation by upregulating the expression and phosphorylation of gp130. While mRNA expression of STAT3 was unchanged, phosphorylation of STAT3-Tyr705 gradually increased. Application of small interference RNA (siRNA) for STAT3 suppressed GFAP expression even in the presence of APP. Treatment with siRNA or inhibitor, AG490, of JAK1 efficiently suppressed STAT3 phosphorylation and GFAP expression. Upregulation of CNTF was observed in either short- or long-term treatment with sAPPα. RNA's interference of CNTF dose-dependently inhibited GFAP expression upregulated by treatment with sAPPα. This study suggests that the IL-6/gp130 signaling pathway is involved in sAPPα-induced glial differentiation of NPCs. Although further investigation is needed, this study may provide insight into the mechanism of glial differentiation of NPCs under pathological conditions in Alzheimer's disease or Down syndrome.
Subject(s)
Amyloid beta-Protein Precursor/physiology , Cell Differentiation/physiology , Cytokine Receptor gp130/metabolism , Neuroglia/cytology , Neuroglia/metabolism , Neurons/metabolism , Signal Transduction/physiology , Stem Cells/metabolism , Cell Line , Cytokine Receptor gp130/physiology , Humans , Neurons/cytology , Protein Structure, Tertiary/physiology , Stem Cells/cytologyABSTRACT
The use of stem cells for neuroreplacement therapy is no longer science fiction - it is science fact. We have succeeded in producing neural cells in the brain using both neural and mesenchymal stem cell transplantation and even systemic injection using a small molecular compound. We have seen the improvement of cognitive function in animal models following the application of these stem cell technologies. These results may promise a bright future for stem cell based neuroreplacement therapies for neurodegenerative diseases including Alzheimer's disease (AD). However, we have to consider the pathophysiological environments of individual diseases before clinical applications can be introduced. We must find the factors in the pathology that may affect stem cell biology and overcome the negative effects on neuroreplacement. Here, we discuss not only the potential for therapeutic applications of stem cell strategies in neuropathological conditions, but also how to overcome the adverse effects on the biology of stem cells due to the factors that are altered under AD pathology.
Subject(s)
Alzheimer Disease/therapy , Stem Cell Transplantation , Stem Cells/physiology , Alzheimer Disease/psychology , Amyloid beta-Protein Precursor/metabolism , Animals , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Cognition/physiology , Humans , Mice , Neurons/drug effects , Neurons/physiology , Physostigmine/analogs & derivatives , Physostigmine/pharmacology , Physostigmine/therapeutic use , RatsABSTRACT
Subjects performed timing and sequencing tasks under separate (single-task) and concurrent (dual-task) conditions in two experiments. The timing task required the subjects to generate a series of 5-sec temporal productions. The sequencing task in Experiment 1 involved verifying reasoning statements that described the ordering of a pair of letters. The task in Experiment 2 involved monitoring a familiar event sequence and detecting omissions in that sequence. Comparisons of single-task and dual-task conditions showed a pattern of bidirectional interference. In each experiment, the concurrent sequencing task caused temporal productions to become more variable and longer. The concurrent timing task interfered with sequencing by lengthening response times to the reasoning statements (Experiment 1) and by lengthening response times to sequence omissions and reducing sensitivity at detecting the omissions (Experiment 2). The results suggest that time perception and sequence perception are related cognitive processes that rely on a common set of attentional resources.
