Dementia model mice exhibited improvements of neuropsychiatric symptoms as well as cognitive dysfunction with neural cell transplantation - PubMed (original) (raw)
Dementia model mice exhibited improvements of neuropsychiatric symptoms as well as cognitive dysfunction with neural cell transplantation
Masanori A Murayama et al. Exp Anim. 2021.
Abstract
Elderly patients with dementia suffer from cognitive dysfunctions and neuropsychiatric symptoms (NPS) such as anxiety and depression. Alzheimer's disease (AD) is a form of age-related dementia, and loss of cholinergic neurons is intimately associated with development of AD symptoms. We and others have reported that neural cell transplantation ameliorated cognitive dysfunction in AD model mice. It remains largely unclear whether neural cell transplantation ameliorates the NPS of AD. It would be interesting to determine whether NPS correlates with cognitive dysfunctions before and after neural cell transplantation in AD model mice. Based on the revalidation of our previous data from a Morris water maze test, we found that neural cell transplantation improved anxiety and depression significantly and marginally affected locomotion activity in AD mice. A correlation analysis revealed that the spatial learning function of AD mice was correlated with their NPS scores both before and after cell transplantation in a similar manner. In contrast, in the mice subjected to cell transplantation, spatial reference memory function was not correlated with NPS scores. These results suggested the neural cell transplantation in the AD model mice significantly improved NPS to the same degree as cognitive dysfunctions, possibly via distinct mechanisms, such as the cholinergic and GABAergic systems.
Keywords: Alzheimer’s disease; PDAPP Tg mice; neural transplantation; neuropsychiatric symptoms.
Conflict of interest statement
The authors declare no competing financial interest.
Figures
Fig. 1.
Schematic representations of human iPS cell-derived neural cell induction and functional assessment by Morris water maze test. (A) Neural induction and transplantation of of hiPS cells. Undifferentiated hiPS cells maintained with mouse embryonic fibroblasts were developed into EBs by 4-day floating culture. To differentiate neural cells, EBs were stimulated with RA, NOG, and SHH at days 5 and 7 (Stim) on a fibronectin (FN)-coated plate. The cells contained neural stem/progenitor cells (NSPCs), as previously reported. For measuring neurotransmitter secretion, culture supernatants of NSPCs were collected at days 5, 8, and 15 for applying ELISA. At day 8, NSPCs were transplanted into PDAPP Tg mice (n=28). Cognitive functions of the grafted PDAPP Tg mice were assessed by MWM test before (1st trial: from day −6 to day −2) and after (2nd trial: from day 22 to day 26) transplantation. (B) The MWM was conducted using a circular pool (diameter: 100 cm) with opaque water and a plastic escape platform (diameter: 15 cm). A 10-cm-wide banded zone along the wall was defined as the peripheral area for behavioral analysis. (C–E) Mice were subjected to the MWM test for 6 consecutive days as follows: (C) visible test on the first day using a platform visualized with a black bottle; (D) hidden test on 4 consecutive days using a platform without the black bottle submerged below the surface of the opaque water; and (E) probe test on the last day under the same conditions except that the platform was removed. The swimming trajectory was monitored by a CCD camera and recorded with a PC. (F) Picture of the experimental equipment for the MWM test.
Fig. 2.
Neural cell transplantation ameliorated behavioral and neuropsychiatric symptoms of PDAPP Tg mice in the visible test. Behavioral and psychological symptoms in PDAPP Tg mice before (1st, in white) and after (2nd, in red) neural cell transplantation were assessed by the visible test with the following parameters: (A) escape latency for motivation to escape the water, (B) thigmotaxis for anxiety, (C) freezing time for depression, and (D) moving speed for locomotion activity. Average and SEM values are shown. **P<0.01; ***P<0.001. (E, F) A correlation analysis was conducted to examine the correlation between the following parameters in the PDAPP Tg mice with neural cell transplantation: (E) escape latency and thigmotaxis and (F) escape latency and freezing time. Motivation to escape the water was correlated with anxiety and depression. Correlation coefficients are indicated as r value. A correlation coefficient of r≥0.6 with a P value <0.001 was considered to indicate strong correlation and was indicated in red.
Fig. 3.
Neural cell transplantation ameliorated spatial learning function in PDAPP Tg mice, which was correlated with neuropsychiatric symptoms in the hidden test. Spatial learning function in PDAPP Tg mice before (1st, in white) and after (2nd, in red) neural cell transplantation was assessed by the hidden test with the following parameters: (A) escape latency for spatial learning function, (B) thigmotaxis for anxiety, (C) freezing time for depression, and (D) moving speed for locomotion activity. Average and SEM values are shown. ***P<0.001. (E, F) A correlation analysis was conducted to examine the correlation between the following parameters in the PDAPP Tg mice with neural cell transplantation: (E) escape latency and thigmotaxis and (F) escape latency and freezing time. Spatial learning function after neural cell transplantation was correlated with anxiety and depression. Correlation coefficients are indicated as r value. A correlation coefficient of r≥0.6 with a P value <0.001 was considered to indicate strong correlation and was indicated in red.
Fig. 4.
Neural transplantation ameliorated spatial memory function in PDAPP Tg mice, which was not correlated with neuropsychiatric symptoms in the probe test. Spatial memory function in PDAPP Tg mice before (1st, in white) and after (2nd, in red) neural transplantation was assessed by the probe test with the following parameters: (A) amounts of time in the targeted quadrant and untargeted quadrants for spatial reference memory function, (B) thigmotaxis for anxiety, (C) freezing time for depression, and (D) moving speed for locomotion activity. Average and SEM values are shown. *P<0.05; ***P<0.001. (E, F) A correlation analysis was conducted to examine the correlation between the following parameters in the PDAPP Tg mice with neural cell transplantation: (E) time in targeted quadrant and thigmotaxis and (F) time in targeted quadrant and freezing time. Spatial reference memory function was not correlated anxiety and depression after neural cell transplantation. Correlation coefficients are indicated as r value. A correlation coefficient of r≤−0.6 or r≥0.6 with a P value <0.001 was considered to indicate strong correlation, and no strong correlation was found among the parameters.
Fig. 5.
Neural cells derived from human iPS cells differentiated in GABA-secreting and acetylcholine-secreting neurons. Culture supernatants of neural cell induction cultures were collected on days 5, 8, and 15. GABA (A) and acetylcholine (B) levels were measured by ELISA (n=8). Average and SEM values are shown. *P<0.05; **P<0.01; ***P<0.001.
Fig. 6.
The broader effects of human iPS cell-derived neural cell transplantation on dementia model mice. The grafted hiPS cell-derived neural cells differentiated into cholinergic (white circle) and GABAergic neurons (black circle). The cholinergic neurons migrated to the hippocampus, and the GABAergic neurons migrated to the cerebral cortex. These neural cells improved cognitive dysfunctions, such as spatial learning dysfunction and spatial reference memory dysfunction, and NPS, such as anxiety and depression. Spatial learning function was correlated with the NPS scores. Spatial reference memory function was not correlated with the NPS scores.
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