Cell therapy for Alzheimer’s disease using induced pluripotent stem cells

Currently, over 35 million individuals worldwide suffer from Alzheimer's disease (AD), the most prevalent type of senile dementia in the elderly population. AD imposes a tremendous socio-political and economic threat due to its devastating nature, monetary cost, and the lack of effective therapies. Over the past few years, the potential use of stem cells to treat brain damage has received growing attention. Specifically, the derivation of induced pluripotent stem cells (iPSCs) from somatic cells has been suggested as a new promising cell therapy for neurodegenerative diseases such as AD. However, to date, this approach has not been tested in AD animal models. Accordingly, the main goal of this PhD thesis was evaluate the potential benefits of mouse iPSC transplantation on AD progression. We generated iPSCs from mouse tail-tip fibroblasts. These iPSCs express pluripotency marker genes and were able to differentiate into cells that express markers for the three primitive germ layers of the embryo. Neural precursor cells (NPCs), able to produce the principal central nervous system (CNS) cell types, were then produced from iPSCs, termed as iPSC-NPCs. These iPSC-NPCs, which express markers typically observed in NPCs, were stereotactically injected into the hippocampus of an aged, transgenic mice model that develops age-related and progressive AD related abnormalities (3xTg-AD). After 2 month, we found that transplanted iPSC-NPCs were able to engraft and differentiate into neurons, astrocytes and oligodendrocytes. Remarkably, iPSC-NPCs transplanted 3xTg-AD mice improved cognitive impairment and hippocampal synaptic transmission and plasticity. Transplanted mice also showed a decrease in AD pathology including Aβ plaque number, hyper-phosphorylated tau and astrogliosis. Considering that the low number of engrafted iPSC-NPCs survived and differentiated on the mouse brain, the beneficial effects attributed to iPSC-NPCs transplantation could be due, in part, to mechanisms alternative to cell replacement, often referred to as a “bystander” effect, including a decrease in inflammation and the secretion of bioactive factors such as brain-derived neurotrophic factor (BDNF) and Aβ degrading enzymes. Significantly, no tumor formation was observed in any iPSC-NPCs-injected mice. The results showed here suggest that stem cell therapy in the form of iPSC-NPCs could be a potentially beneficial and secure treatment for aged individuals already clinically diagnosed with insidious neurodegenerative diseases, such as AD.