Effect of systemic transplantation of bone marrow‐derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice

Abstract

Aims Mesenchymal stem cells (MSC) have recently attracted interest as a potential basis for a cell‐based therapy of AD. We investigated the putative immune‐modulatory effects in neuroinflammation of systemic transplantation of MSC into APP/PS1 transgenic mice. Methods 106 MSC were injected into APP/PS1 mice via the tail vein and histological analysis was performed for microglia and amyloid (pE3‐Aβ) plaque numbers, glial distribution and pE3‐Aβ plaque size. In addition, a biochemical analysis by qPCR for pro‐inflammatory, chemoattractant and neurotrophic factors was performed. Results MSC are associated with pE3‐Aβ plaques. The effects of transplantation on microglia‐associated pathology could be observed after 28 days. Animals showed a reduction in microglial numbers in the cortex and in microglia size. Gene expression was reduced for TNF‐α, IL‐6, MCP‐1, and for NGF, in MSC recipients. Also, we investigated for the first time and found no changes in expression of IL‐10, CCR5, BDNF, VEGF and IFNγ. PTGER2 expression levels were increased in the hippocampus but were reduced in the cortex of MSC recipients. While there were no transplant‐related changes in pE3‐Aβ plaque numbers, a reduction in the size of pE3‐Aβ plaques was observed in the hippocampus of transplant recipients. Conclusion This is the first study to show reduction in pE3‐Aβ plaque size. pE3‐Aβ plaques have gained attention as potential key participants in AD due to their increased aggregation propensity, the possibility for the initial seeding event, resistance against degradation and neurotoxicity. These findings support the hypothesis that MSC‐transplants may affect AD pathology via an immune‐modulatory function that includes an effect on microglial cells.

Human Umbilical Cord Stem Cell Xenografts Improve Cognitive Decline and Reduce the Amyloid Burden in a Mouse Model of Alzheimer's Disease

“…Whereas, significant difference were observed with microglia immunoreactivity in the cortex and in the hippocampus of treated versus controls. Recently, similar data obtained by systemic transplantation of bone marrow-derived mesenchymal stem cells in an AD mouse model were reported, supporting our findings [26]. …”

Microglia‐targeted stem cell therapies for Alzheimer disease: A preclinical data review

“…MSCs applied in AD rodent studies have been isolated from bone marrow (BM‐MSCs) (Naaldijk et al, ), adipose tissue (ADSCs) (Ma et al, ), umbilical cord Wharton's jelly (WJ‐MSCs) (Xie et al, ), umbilical cord blood (UCB‐MSCs) (Lee H. J., et al, ), and amniotic membrane (AMSCs) (Kim K. S., et al, ). They have captured considerable scientific interest for their tissue repair and immunomodulation (Li, Guo, & Ikehara, ; Tolar, Le Blanc, Keating, & Blazar, ) and possess the capacity to transdifferentiate into a variety of cell types (Phinney & Prockop, ).…”

“…According to the studies reviewed in Table , one study shows that microglial morphology changes from a ramified state to an amoeboid state after transplantation of stem cells in AD mice (Lee J. K., et al, ), which seems to favor microglial phagocytosis. However, microglia have also been shown to become more ramified with more processes per cell after stem cell therapy in AD rats (Naaldijk et al, ), which is associated with the ability of microglia to screen their microenvironment and protect hippocampal neurons (Vinet et al, ). Conversely, some studies indicate that transplanted stem cells strongly induce microglial activation, as characterized by an increased number of microglia (Kim J. Y., et al, ; Kim K. S., et al, ; Lee J. K., et al, ; Lee J. K., et al, ; Lee H. J., et al, ; Ma et al, ; Xie et al, ).…”

Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases

“…After injection in the tail vein of APP/PS1 mice, BMSCs were found in the hippocampus and cerebral cortex, mainly around Aβ plaques (Naaldijk et al, ). A reduction was induced in the dimensions of pyroglutamate‐beta amyloid plaque at the hippocampal level.…”