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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.


hNSCs rescued neuronal loss in APP/PS1 mice. (A) Nissl-staining images in the frontal cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (B) Comparisons of neuronal counts per view (40×) in the hippocampal CA1, CA3, DG regions and cortical pyramidal cellular layer (PCL) and multiform cellular layers (MCL) areas among three groups of mice. There was no significant difference in neuronal counts between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.
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Figure 4: hNSCs rescued neuronal loss in APP/PS1 mice. (A) Nissl-staining images in the frontal cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (B) Comparisons of neuronal counts per view (40×) in the hippocampal CA1, CA3, DG regions and cortical pyramidal cellular layer (PCL) and multiform cellular layers (MCL) areas among three groups of mice. There was no significant difference in neuronal counts between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.

Mentions: Nissl staining was conducted to assess effects of hNSCs on neuronal loss in AD brain; representative images are shown in Figure 4. Compared with WT mice, PBS group mice showed typical Alzheimer’s pathology, including neuron loss, nucleus shrinkage or disappearance of Nissl bodies in the frontal cortex and hippocampus (Figure 4A). Compared with PBS group, the neuronal number was significantly increased and the cell organization was notably improved in the hippocampal CA1, CA3, DG regions and cortical PCL and MCL areas of NSC group mice (ANOVA with post hoc Tukey’s test, all p < 0.05; Figure 4B). However, no notable difference was observed in neuronal counts between NSC and WT group mice (all p > 0.05). These results imply that hNSCs improved the number and structure of neurons in AD mice brains.


Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer ’ s Disease by Enhancing Neuronal Connectivity and Metabolic Activity
hNSCs rescued neuronal loss in APP/PS1 mice. (A) Nissl-staining images in the frontal cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (B) Comparisons of neuronal counts per view (40×) in the hippocampal CA1, CA3, DG regions and cortical pyramidal cellular layer (PCL) and multiform cellular layers (MCL) areas among three groups of mice. There was no significant difference in neuronal counts between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.
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Related In: Results  -  Collection

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Figure 4: hNSCs rescued neuronal loss in APP/PS1 mice. (A) Nissl-staining images in the frontal cortex and hippocampus of PBS, NSC group and WT mice. Scale bar: 20 μm. (B) Comparisons of neuronal counts per view (40×) in the hippocampal CA1, CA3, DG regions and cortical pyramidal cellular layer (PCL) and multiform cellular layers (MCL) areas among three groups of mice. There was no significant difference in neuronal counts between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.
Mentions: Nissl staining was conducted to assess effects of hNSCs on neuronal loss in AD brain; representative images are shown in Figure 4. Compared with WT mice, PBS group mice showed typical Alzheimer’s pathology, including neuron loss, nucleus shrinkage or disappearance of Nissl bodies in the frontal cortex and hippocampus (Figure 4A). Compared with PBS group, the neuronal number was significantly increased and the cell organization was notably improved in the hippocampal CA1, CA3, DG regions and cortical PCL and MCL areas of NSC group mice (ANOVA with post hoc Tukey’s test, all p < 0.05; Figure 4B). However, no notable difference was observed in neuronal counts between NSC and WT group mice (all p > 0.05). These results imply that hNSCs improved the number and structure of neurons in AD mice brains.

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.