Mesenchymal Stem Cells Preserve Working Memory in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Abstract

The transplantation of stem cells may have a therapeutic effect on the pathogenesis and progression of neurodegenerative disorders. In the present study, we transplanted human mesenchymal stem cells (MSCs) into the lateral ventricle of a triple transgenic mouse model of Alzheimer´s disease (3xTg-AD) at the age of eight months. We evaluated spatial reference and working memory after MSC treatment and the possible underlying mechanisms, such as the influence of transplanted MSCs on neurogenesis in the subventricular zone (SVZ) and the expression levels of a 56 kDa oligomer of amyloid β (Aβ*56), glutamine synthetase (GS) and glutamate transporters (Glutamate aspartate transporter (GLAST) and Glutamate transporter-1 (GLT-1)) in the entorhinal and prefrontal cortices and the hippocampus. At 14 months of age we observed the preservation of working memory in MSC-treated 3xTg-AD mice, suggesting that such preservation might be due to the protective effect of MSCs on GS levels and the considerable downregulation of Aβ*56 levels in the entorhinal cortex. These changes were observed six months after transplantation, accompanied by clusters of proliferating cells in the SVZ. Since the grafted cells did not survive for the whole experimental period, it is likely that the observed effects could have been transiently more pronounced at earlier time points than at six months after cell application.

Cell motility and migration as determinants of stem cell efficacy

“…Moreover, we show that superior efficacy does not require enhanced in vivo graft cell proliferation . INA of highly migrating SC subpopulations combines the advantages of non-invasiveness and greater efficacy, where poor cell transplant survival might become relevant in Alzheimer's dementia [42] .…”

Effects of mesenchymal stem cells transplantation on cognitive deficits in animal models of Alzheimer’s disease: A systematic review and meta‐analysis

“…Firstly, previous studies verified that the neuroprotective and neurogenesis effect of MSCs was related to the release of neurotrophins such as acetylcholine (Ach) and nerve growth factor (NGF) (Fahnestock, Garzon, Holsinger, & Michalski, ; Fumagalli, Racagni, & Riva, ; Peng, Wuu, Mufson, & Fahnestock, ; Siegel & Chauhan, ) .In addition, MSCs also upregulate the expression of the anti‐apoptotic factors to protect neurons. Secondly, many evidences proved that MSCs attenuate the syndrome of AD and prevent the progression of the disease by expressing antioxidant enzymes, alleviating oxidative stress (Chiang, Nicol, Cheng, Lin, & Yen, ; Ruzicka, Kulijewicz‐Nawrot, Rodrigez‐Arellano, Jendelova, & Sykova, ; Xie et al., ; Yang, Xie, et al., ). Thirdly, inhibition of activated microglia and decreased levels of Aβ plays a critical role in MSC‐induced cognitive improvement (Woodruffpak, ).…”

Ginsenoside Rg1 Ameliorates Behavioral Abnormalities and Modulates the Hippocampal Proteomic Change in Triple Transgenic Mice of Alzheimer’s Disease

“…The distinctive histopathological hallmarks of AD are extracellular senile plaques consisted of β -amyloid (A β ) peptides, intracellular neurofibrillary tangles, neuronal loss, and synapse injury in some vulnerable regions such as the hippocampus [ 4 – 6 ]. In addition to cognitive impairment, neuropsychiatric symptoms such as depression-like behavior were prevalent in AD cases [ 7 – 10 ].…”