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Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer ’ s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer’s disease (AD), the most frequent type of dementia, is featured by Aβ pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC) transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs) into bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD to test the effects of hNSC transplantation on Alzheimer’s behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system (CNS). The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Aβ plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore, in vivo magnetic resonance spectroscopy (MRS) showed that hNSC-treated mice had notably increased levels of N-acetylaspartate (NAA) and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer’s cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation can be a possible and feasible strategy for treating patients with AD.

No MeSH data available.


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hNSCs slightly alleviated Aβ pathology in APP/PS1 mice. (A) Analysis of ELISA results. The soluble and insoluble Aβs were significantly higher in the frontal cortex and hippocampus of the PBS and NSC group than that of WT mice (#p < 0.05; ##p < 0.01 vs. WT mice). Though soluble Aβs was significantly reduced in the NSC group (*p < 0.05; **p < 0.01 vs. the PBS group), no significant difference was found in insoluble Aβs between the NSC and PBS group (ns. = p > 0.05). (B) Representative 6E10-staining images in the cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (C) There were no significant difference in the Aβ plaque number and area in the frontal cortex and hippocampus between the PBS and NSC group (ns. = p > 0.05). However, the plaque intensity was significantly reduced in the NSC group (*p < 0.05, vs. the PBS group).
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Figure 3: hNSCs slightly alleviated Aβ pathology in APP/PS1 mice. (A) Analysis of ELISA results. The soluble and insoluble Aβs were significantly higher in the frontal cortex and hippocampus of the PBS and NSC group than that of WT mice (#p < 0.05; ##p < 0.01 vs. WT mice). Though soluble Aβs was significantly reduced in the NSC group (*p < 0.05; **p < 0.01 vs. the PBS group), no significant difference was found in insoluble Aβs between the NSC and PBS group (ns. = p > 0.05). (B) Representative 6E10-staining images in the cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (C) There were no significant difference in the Aβ plaque number and area in the frontal cortex and hippocampus between the PBS and NSC group (ns. = p > 0.05). However, the plaque intensity was significantly reduced in the NSC group (*p < 0.05, vs. the PBS group).

Mentions: To assess effects of hNSCs on Aβ pathology in AD brain, the Aβ level and plaque burden were both assessed in the NSC, PBS and WT group mice. Because insoluble Aβs were intermediates from soluble Aβs to plaques, two Aβ forms were tested separately, and the results are summarized in Figure 3A. Compared with WT mice, soluble and insoluble Aβ1–40 and Aβ1–42 peptides were all significantly increased in the frontal cortex and hippocampus of PBS group mice (ANOVA with post hoc Tukey’s test, all p < 0.05). Compared with PBS group, soluble Aβ1–40 and Aβ1–42 were significantly reduced in the frontal cortex and hippocampus of NSC group mice (all p < 0.05), to the equivalent levels as exhibited by WT mice. However, insoluble Aβ1–40 and Aβ1–42 were still significantly higher in the cortex and hippocampus of NSC group mice than that of WT mice (all p < 0.05), and there was no significant difference between the PBS and NSC group mice (all p > 0.05). These results suggest that hNSCs significantly reduced soluble but not insoluble Aβ1–40 and Aβ1–42 levels in the cortex and hippocampus of AD mice.


Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer ’ s Disease by Enhancing Neuronal Connectivity and Metabolic Activity
hNSCs slightly alleviated Aβ pathology in APP/PS1 mice. (A) Analysis of ELISA results. The soluble and insoluble Aβs were significantly higher in the frontal cortex and hippocampus of the PBS and NSC group than that of WT mice (#p < 0.05; ##p < 0.01 vs. WT mice). Though soluble Aβs was significantly reduced in the NSC group (*p < 0.05; **p < 0.01 vs. the PBS group), no significant difference was found in insoluble Aβs between the NSC and PBS group (ns. = p > 0.05). (B) Representative 6E10-staining images in the cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (C) There were no significant difference in the Aβ plaque number and area in the frontal cortex and hippocampus between the PBS and NSC group (ns. = p > 0.05). However, the plaque intensity was significantly reduced in the NSC group (*p < 0.05, vs. the PBS group).
© Copyright Policy
Related In: Results  -  Collection

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Figure 3: hNSCs slightly alleviated Aβ pathology in APP/PS1 mice. (A) Analysis of ELISA results. The soluble and insoluble Aβs were significantly higher in the frontal cortex and hippocampus of the PBS and NSC group than that of WT mice (#p < 0.05; ##p < 0.01 vs. WT mice). Though soluble Aβs was significantly reduced in the NSC group (*p < 0.05; **p < 0.01 vs. the PBS group), no significant difference was found in insoluble Aβs between the NSC and PBS group (ns. = p > 0.05). (B) Representative 6E10-staining images in the cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (C) There were no significant difference in the Aβ plaque number and area in the frontal cortex and hippocampus between the PBS and NSC group (ns. = p > 0.05). However, the plaque intensity was significantly reduced in the NSC group (*p < 0.05, vs. the PBS group).
Mentions: To assess effects of hNSCs on Aβ pathology in AD brain, the Aβ level and plaque burden were both assessed in the NSC, PBS and WT group mice. Because insoluble Aβs were intermediates from soluble Aβs to plaques, two Aβ forms were tested separately, and the results are summarized in Figure 3A. Compared with WT mice, soluble and insoluble Aβ1–40 and Aβ1–42 peptides were all significantly increased in the frontal cortex and hippocampus of PBS group mice (ANOVA with post hoc Tukey’s test, all p < 0.05). Compared with PBS group, soluble Aβ1–40 and Aβ1–42 were significantly reduced in the frontal cortex and hippocampus of NSC group mice (all p < 0.05), to the equivalent levels as exhibited by WT mice. However, insoluble Aβ1–40 and Aβ1–42 were still significantly higher in the cortex and hippocampus of NSC group mice than that of WT mice (all p < 0.05), and there was no significant difference between the PBS and NSC group mice (all p > 0.05). These results suggest that hNSCs significantly reduced soluble but not insoluble Aβ1–40 and Aβ1–42 levels in the cortex and hippocampus of AD mice.

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer&rsquo;s disease (AD), the most frequent type of dementia, is featured by A&beta; pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC) transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs) into bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD to test the effects of hNSC transplantation on Alzheimer&rsquo;s behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system (CNS). The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although A&beta; plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore, in vivo magnetic resonance spectroscopy (MRS) showed that hNSC-treated mice had notably increased levels of N-acetylaspartate (NAA) and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer&rsquo;s cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation can be a possible and feasible strategy for treating patients with AD.

No MeSH data available.


Related in: MedlinePlus