Placenta-derived mesenchymal stem cells improve memory dysfunction in an Aβ1–42-infused mouse model of Alzheimer’s disease

Abstract

Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of central nervous system (CNS) and are currently being tested in clinical trials for neurological disorders, but preventive mechanisms of placenta-derived MSCs (PD-MSCs) for Alzheimer's disease are poorly understood. Herein, we investigated the inhibitory effect of PD-MSCs on neuronal cell death and memory impairment in Aβ1–42-infused mice. After intracerebroventrical (ICV) infusion of Aβ1–42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. Our results showed that the transplantation of PD-MSCs into Aβ1–42-infused mice significantly improved cognitive impairment, and behavioral changes attenuated the expression of APP, BACE1, and Aβ, as well as the activity of β-secretase and γ-secretase. In addition, the activation of glia cells and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were inhibited by the transplantation of PD-MSCs. Furthermore, we also found that PD-MSCs downregulated the release of inflammatory cytokines as well as prevented neuronal cell death and promoted neuronal cell differentiation from neuronal progenitor cells in Aβ1–42-infused mice. These data indicate that PD-MSC mediates neuroprotection by regulating neuronal death, neurogenesis, glia cell activation in hippocampus, and altering cytokine expression, suggesting a close link between the therapeutic effects of MSCs and the damaged CNS in Alzheimer's disease.

Applications of the Keap1–Nrf2 system for gene and cell therapy

“…The challenging nature of stem cell therapy for AD is described in several excellent review papers published in recent years [137,138] . Despite these obstacles, numerous studies have demonstrated improvements in learning and memory by transplanting neural stem cells to the brains of rodents modeling AD [139][140][141][142][143][144][145][146][147][148] . In addition, transplantation of adipose-derived stem cells to mouse models of AD have shown restoration of memory deficits [149][150][151] and human umbilical cord-derived MSCs that have been differentiated to neuron-like cells also improve cognitive function in AD mouse models [152,153] .…”

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats

“…The hippocampal CA1 area was removed for further analysis of the protein expression of mTOR and downstream pathways and the levels of PICs. As previously reported by others [9, 10], in our present study αβ 1-42 was infused unilaterally via the ICV. It is noted that we did not observe significant differences in expression of mTOR and its downstream pathways between the right and left sides of the CA1 region in our preliminary experiments.…”

Strategies to improve the migration of mesenchymal stromal cells in cell therapy

“…MSCs have been used to treat various CNS disorders in preclinical and clinical studies, such as spinal cord and traumatic brain injury [116][117][118] , ischemic stroke [31,40,56,62,69,97,[119][120][121][122][123] , intracranial hemorrhage (ICH) [124] , Parkinson's disease [125,126] , multiple sclerosis [127] , experimental autoimmune encephalomyelitis (EAE) [47,128,129] , amyotrophic lateral sclerosis [130,131] , Alzheimer's disease [132] , Huntington's disease [133][134][135] , and so on. Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs.…”