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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 improved nerve fibers in APP/PS1 mice brains. (A) Microtubule associated protein 2 (MAP2)-staining sections in the brains of PBS, NSC group and WT mice, and quantification of MAP2-staining in the frontal cortex and hippocampus of three groups of mice. There was no significant difference in % area of neuropil between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group. Scale bar: 20 μm. (B) Ultrastructure analysis showed the enlargement and disorganization of unmyelinated nerves in the cortex and hippocampus of PBS group mice; the damage was alleviated in NSC group. Likewise, myelinated nerves maintained relatively intact in myelin sheath in NSC group and WT mice. Arrow indicates the nerve fibers. Scale bar: 1 μm.
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Figure 6: hNSCs improved nerve fibers in APP/PS1 mice brains. (A) Microtubule associated protein 2 (MAP2)-staining sections in the brains of PBS, NSC group and WT mice, and quantification of MAP2-staining in the frontal cortex and hippocampus of three groups of mice. There was no significant difference in % area of neuropil between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group. Scale bar: 20 μm. (B) Ultrastructure analysis showed the enlargement and disorganization of unmyelinated nerves in the cortex and hippocampus of PBS group mice; the damage was alleviated in NSC group. Likewise, myelinated nerves maintained relatively intact in myelin sheath in NSC group and WT mice. Arrow indicates the nerve fibers. Scale bar: 1 μm.

Mentions: Synaptic injury is often associated with damage of neuronal dendrites in AD brain. Thus, brain sections were labeled with a MAP2 antibody to assess synapto-dendritic damage (Figure 6). Results showed that NSC and WT group mice exhibited comparable levels of MAP2 immunoreactivity in the frontal cortex and hippocampus (ANOVA with post hoc Tukey’s test, p = 0.316 and p = 0.321 respectively; Figure 6A). Compared with PBS group, NSC group mice exhibited a notable increase in % area of the neuropil covered by MAP2-staining dendrites (p = 0.019; p = 0.010), and there was no significant difference in MAP2 immunoreactivity between NSC group and WT mice (p = 0.316 and p = 0.321 respectively). Ultrastructure analysis showed that unmyelinated nerves appeared enlarged in appearance and mussy in organization in the frontal cortex and hippocampus of PBS group mice, whereas the damage was notably repaired in NSC group mice. Likewise, compared with PBS group, myelinated nerves were relatively intact in myelin sheath in both NSC group and WT mice (Figure 6B).


Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer ’ s Disease by Enhancing Neuronal Connectivity and Metabolic Activity
hNSCs improved nerve fibers in APP/PS1 mice brains. (A) Microtubule associated protein 2 (MAP2)-staining sections in the brains of PBS, NSC group and WT mice, and quantification of MAP2-staining in the frontal cortex and hippocampus of three groups of mice. There was no significant difference in % area of neuropil between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group. Scale bar: 20 μm. (B) Ultrastructure analysis showed the enlargement and disorganization of unmyelinated nerves in the cortex and hippocampus of PBS group mice; the damage was alleviated in NSC group. Likewise, myelinated nerves maintained relatively intact in myelin sheath in NSC group and WT mice. Arrow indicates the nerve fibers. Scale bar: 1 μm.
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Figure 6: hNSCs improved nerve fibers in APP/PS1 mice brains. (A) Microtubule associated protein 2 (MAP2)-staining sections in the brains of PBS, NSC group and WT mice, and quantification of MAP2-staining in the frontal cortex and hippocampus of three groups of mice. There was no significant difference in % area of neuropil between the NSC group and WT mice (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group. Scale bar: 20 μm. (B) Ultrastructure analysis showed the enlargement and disorganization of unmyelinated nerves in the cortex and hippocampus of PBS group mice; the damage was alleviated in NSC group. Likewise, myelinated nerves maintained relatively intact in myelin sheath in NSC group and WT mice. Arrow indicates the nerve fibers. Scale bar: 1 μm.
Mentions: Synaptic injury is often associated with damage of neuronal dendrites in AD brain. Thus, brain sections were labeled with a MAP2 antibody to assess synapto-dendritic damage (Figure 6). Results showed that NSC and WT group mice exhibited comparable levels of MAP2 immunoreactivity in the frontal cortex and hippocampus (ANOVA with post hoc Tukey’s test, p = 0.316 and p = 0.321 respectively; Figure 6A). Compared with PBS group, NSC group mice exhibited a notable increase in % area of the neuropil covered by MAP2-staining dendrites (p = 0.019; p = 0.010), and there was no significant difference in MAP2 immunoreactivity between NSC group and WT mice (p = 0.316 and p = 0.321 respectively). Ultrastructure analysis showed that unmyelinated nerves appeared enlarged in appearance and mussy in organization in the frontal cortex and hippocampus of PBS group mice, whereas the damage was notably repaired in NSC group mice. Likewise, compared with PBS group, myelinated nerves were relatively intact in myelin sheath in both NSC group and WT mice (Figure 6B).

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