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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.


Related in: MedlinePlus

Transplantation of human brain-derived neural stem cells (hNSCs) into hippocampal CA1 region of amyloid precursor protein (APP)/presenilin 1 (PS1; Alzheimer’s disease, AD) mice. (A) Schematic drawing of a typical coronal brain section, illustrating the distribution of engrafted green fluorescent protein (GFP)-labeled cells (green dots). Asterisks represent the transplantation sites. Lowercase letters indicate sites where corresponding images (B–G) were taken. (B,C) Transplanted hNSCs engrafted into the hippocampus, and they migrated extensively into corpus callosum (D), frontal cortex (E), thalamus (F) and external capsule (G). (H,I) GFP-labeled hNSCs co-localized well with 4′,6-diamidino-2-phenylindole (DAPI; white arrow). Some of hNSCs differentiated into GFAP-astrocytes or mature neurons (J–R). There was no significant difference in counts between GFP-labeled and GFP/DAPI co-labeled cells (ns. = p > 0.05). Scale bar: 50 μm.
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Figure 1: Transplantation of human brain-derived neural stem cells (hNSCs) into hippocampal CA1 region of amyloid precursor protein (APP)/presenilin 1 (PS1; Alzheimer’s disease, AD) mice. (A) Schematic drawing of a typical coronal brain section, illustrating the distribution of engrafted green fluorescent protein (GFP)-labeled cells (green dots). Asterisks represent the transplantation sites. Lowercase letters indicate sites where corresponding images (B–G) were taken. (B,C) Transplanted hNSCs engrafted into the hippocampus, and they migrated extensively into corpus callosum (D), frontal cortex (E), thalamus (F) and external capsule (G). (H,I) GFP-labeled hNSCs co-localized well with 4′,6-diamidino-2-phenylindole (DAPI; white arrow). Some of hNSCs differentiated into GFAP-astrocytes or mature neurons (J–R). There was no significant difference in counts between GFP-labeled and GFP/DAPI co-labeled cells (ns. = p > 0.05). Scale bar: 50 μm.

Mentions: Two regions of interest (ROI) sizing 20 mm3 × 20 mm3 × 18 mm3 were located on the right hippocampus and adjacent cortical region (Figure 1). The ROI location was placed on the coronal, axial and sagittal planes of mice brains. To control the consistency of ROI placements two experienced investigators simultaneously checked the location. MRS data was collected using point-resolved water suppression pulse sequence (PRESS) as following parameters: TR = 2500 s, TE = 20 ms, EF = 1000, T = 40 min. The obtained data was processed with the Bruker processing software 2D WIN-NMR (Bruker-Franzen Analytic, Germany). After baseline correction and adjustment, area under the peak of each metabolite was calculated automatically using the NUTS-NMR Utility Transform Software (AcornNMR, Livermore, CA, USA). The evaluated metabolites included NAA, Cho, Glu, mI and Cr. Because Cr is consistent in various diseases, it was used as the internal standard to calculate NAA/Cr, Cho/Cr, Glu/Cr and mI/Cr in this study.


Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer ’ s Disease by Enhancing Neuronal Connectivity and Metabolic Activity
Transplantation of human brain-derived neural stem cells (hNSCs) into hippocampal CA1 region of amyloid precursor protein (APP)/presenilin 1 (PS1; Alzheimer’s disease, AD) mice. (A) Schematic drawing of a typical coronal brain section, illustrating the distribution of engrafted green fluorescent protein (GFP)-labeled cells (green dots). Asterisks represent the transplantation sites. Lowercase letters indicate sites where corresponding images (B–G) were taken. (B,C) Transplanted hNSCs engrafted into the hippocampus, and they migrated extensively into corpus callosum (D), frontal cortex (E), thalamus (F) and external capsule (G). (H,I) GFP-labeled hNSCs co-localized well with 4′,6-diamidino-2-phenylindole (DAPI; white arrow). Some of hNSCs differentiated into GFAP-astrocytes or mature neurons (J–R). There was no significant difference in counts between GFP-labeled and GFP/DAPI co-labeled cells (ns. = p > 0.05). Scale bar: 50 μm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5120101&req=5

Figure 1: Transplantation of human brain-derived neural stem cells (hNSCs) into hippocampal CA1 region of amyloid precursor protein (APP)/presenilin 1 (PS1; Alzheimer’s disease, AD) mice. (A) Schematic drawing of a typical coronal brain section, illustrating the distribution of engrafted green fluorescent protein (GFP)-labeled cells (green dots). Asterisks represent the transplantation sites. Lowercase letters indicate sites where corresponding images (B–G) were taken. (B,C) Transplanted hNSCs engrafted into the hippocampus, and they migrated extensively into corpus callosum (D), frontal cortex (E), thalamus (F) and external capsule (G). (H,I) GFP-labeled hNSCs co-localized well with 4′,6-diamidino-2-phenylindole (DAPI; white arrow). Some of hNSCs differentiated into GFAP-astrocytes or mature neurons (J–R). There was no significant difference in counts between GFP-labeled and GFP/DAPI co-labeled cells (ns. = p > 0.05). Scale bar: 50 μm.
Mentions: Two regions of interest (ROI) sizing 20 mm3 × 20 mm3 × 18 mm3 were located on the right hippocampus and adjacent cortical region (Figure 1). The ROI location was placed on the coronal, axial and sagittal planes of mice brains. To control the consistency of ROI placements two experienced investigators simultaneously checked the location. MRS data was collected using point-resolved water suppression pulse sequence (PRESS) as following parameters: TR = 2500 s, TE = 20 ms, EF = 1000, T = 40 min. The obtained data was processed with the Bruker processing software 2D WIN-NMR (Bruker-Franzen Analytic, Germany). After baseline correction and adjustment, area under the peak of each metabolite was calculated automatically using the NUTS-NMR Utility Transform Software (AcornNMR, Livermore, CA, USA). The evaluated metabolites included NAA, Cho, Glu, mI and Cr. Because Cr is consistent in various diseases, it was used as the internal standard to calculate NAA/Cr, Cho/Cr, Glu/Cr and mI/Cr in this study.

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.


Related in: MedlinePlus