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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 rescued recognition, learning and memory function but not anxiety level in APP/PS1 mice. (A) Analysis of open field test (OFT) tests. There was no significant difference in frequencies of mobile, immobile and highly mobile states, as well as % of duration in periphery and central zones between the PBS and NSC group (ns. = p > 0.05), #p < 0.05 vs. wild-type (WT) mice. (B) There was no difference in discrimination index (DI) between the WT and NSC group (ns. = p > 0.05), **p < 0.01 vs. the PBS group. (C) Escape latencies in five training days of the morris water maze (MWM). Significant interactions were found for the latency from training day 2 (*p < 0.05; **p < 0.01), where NSC group mice decreased the latency to the hidden platform. No significant difference in latencies was found between the NSC and WT group (ns. = p > 0.05). (D) Representative training (5th day) and probe traces of mice in three groups. (E) Analysis of the probe test. There was no significant difference in % of distance traveled in target quadrant, mean speed and number of crossings between the WT and NSC group (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.
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Figure 2: hNSCs rescued recognition, learning and memory function but not anxiety level in APP/PS1 mice. (A) Analysis of open field test (OFT) tests. There was no significant difference in frequencies of mobile, immobile and highly mobile states, as well as % of duration in periphery and central zones between the PBS and NSC group (ns. = p > 0.05), #p < 0.05 vs. wild-type (WT) mice. (B) There was no difference in discrimination index (DI) between the WT and NSC group (ns. = p > 0.05), **p < 0.01 vs. the PBS group. (C) Escape latencies in five training days of the morris water maze (MWM). Significant interactions were found for the latency from training day 2 (*p < 0.05; **p < 0.01), where NSC group mice decreased the latency to the hidden platform. No significant difference in latencies was found between the NSC and WT group (ns. = p > 0.05). (D) Representative training (5th day) and probe traces of mice in three groups. (E) Analysis of the probe test. There was no significant difference in % of distance traveled in target quadrant, mean speed and number of crossings between the WT and NSC group (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.

Mentions: The behavioral changes were assessed in all mice before histological examination, the results of which are summarized in Figure 2. The OFT was used to assess the anxiety of AD mice. In the test, both the PBS and NSC group mice exhibited higher frequencies of immobile, mobile and highly mobile states and spent more time in the central zone and lesser time in the periphery zone than WT mice (ANOVA with post hoc Tukey’s test, all p < 0.05; Figure 2A), suggesting that AD mice were more hyperactive and anxious. However, no significant difference was observed between two groups of AD mice in any of the five parameters including mobile frequencies and time spent in each zone (all p > 0.05; Figure 2A). Thus, hNSCs did not significantly alter anxiety level in AD mice. In the NOR task, NSC group mice showed notably higher DI values than PBS group, but there were no significant difference in DI between NSC group and WT mice (ANOVA with post hoc Tukey’s test, p = 0.001 and p = 0.60 respectively; Figure 2B), suggesting that hNSCs restored the impaired recognition in 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 rescued recognition, learning and memory function but not anxiety level in APP/PS1 mice. (A) Analysis of open field test (OFT) tests. There was no significant difference in frequencies of mobile, immobile and highly mobile states, as well as % of duration in periphery and central zones between the PBS and NSC group (ns. = p > 0.05), #p < 0.05 vs. wild-type (WT) mice. (B) There was no difference in discrimination index (DI) between the WT and NSC group (ns. = p > 0.05), **p < 0.01 vs. the PBS group. (C) Escape latencies in five training days of the morris water maze (MWM). Significant interactions were found for the latency from training day 2 (*p < 0.05; **p < 0.01), where NSC group mice decreased the latency to the hidden platform. No significant difference in latencies was found between the NSC and WT group (ns. = p > 0.05). (D) Representative training (5th day) and probe traces of mice in three groups. (E) Analysis of the probe test. There was no significant difference in % of distance traveled in target quadrant, mean speed and number of crossings between the WT and NSC group (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.
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Figure 2: hNSCs rescued recognition, learning and memory function but not anxiety level in APP/PS1 mice. (A) Analysis of open field test (OFT) tests. There was no significant difference in frequencies of mobile, immobile and highly mobile states, as well as % of duration in periphery and central zones between the PBS and NSC group (ns. = p > 0.05), #p < 0.05 vs. wild-type (WT) mice. (B) There was no difference in discrimination index (DI) between the WT and NSC group (ns. = p > 0.05), **p < 0.01 vs. the PBS group. (C) Escape latencies in five training days of the morris water maze (MWM). Significant interactions were found for the latency from training day 2 (*p < 0.05; **p < 0.01), where NSC group mice decreased the latency to the hidden platform. No significant difference in latencies was found between the NSC and WT group (ns. = p > 0.05). (D) Representative training (5th day) and probe traces of mice in three groups. (E) Analysis of the probe test. There was no significant difference in % of distance traveled in target quadrant, mean speed and number of crossings between the WT and NSC group (ns. = p > 0.05), *p < 0.05; **p < 0.01 vs. the PBS group.
Mentions: The behavioral changes were assessed in all mice before histological examination, the results of which are summarized in Figure 2. The OFT was used to assess the anxiety of AD mice. In the test, both the PBS and NSC group mice exhibited higher frequencies of immobile, mobile and highly mobile states and spent more time in the central zone and lesser time in the periphery zone than WT mice (ANOVA with post hoc Tukey’s test, all p < 0.05; Figure 2A), suggesting that AD mice were more hyperactive and anxious. However, no significant difference was observed between two groups of AD mice in any of the five parameters including mobile frequencies and time spent in each zone (all p > 0.05; Figure 2A). Thus, hNSCs did not significantly alter anxiety level in AD mice. In the NOR task, NSC group mice showed notably higher DI values than PBS group, but there were no significant difference in DI between NSC group and WT mice (ANOVA with post hoc Tukey’s test, p = 0.001 and p = 0.60 respectively; Figure 2B), suggesting that hNSCs restored the impaired recognition in 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