Modeling and Therapeutic Strategies of Pluripotent Stem Cells for Alzheimer's Disease
Journal of Stem Cell Research & Therapy
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, which is characterized by a progressive and age-related chronic loss of neurons in extensive brain areas, such as cerebral cortex and hippocampus, one of the most prominent being the basal forebrain cholinergic neurons (BFCN). In clinic, patients suffer from impairment of memory and cognitive function, language breakdown and eventually long-term memory loss. The burden of AD is heavy to patient's families and the
... e society. The pathological findings of AD are senile plaques, neurofibrillary tangles and neuronal cell death. Senile plaques and neurofibrillary tangles are mainly consisted of β-amyloid (Aβ) peptides, which are formed by the cleavage of amyloid precursor protein (APP) by β-and γ-secretase. In the end, accumulation of Aβ peptides in neurons causes neuronal degeneration and cell death [1, 2] . Although previous studies already showed the effects of Aβ peptides on cultured mammal neurons, how Aβ peptides affect human neurons, especially neurons from AD patients, are still not understood. On the other hand, although neurotrophic factors application, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), have showed functional recovery in animal model of AD and several drugs for the treatment of AD has been approved by FDA and have shown the improvement of cognitive function and memory of AD patient, it is still challenge to delay and reverse the neuronal degeneration and cell death    . Neural stem cells (NSCs) have been harvested from mammal brain and used for the therapeutic studies of AD [6, 7] . But, it is difficult to transfer this strategy for clinical application due to limited resource. Recent progress in pluripotent stem cells biology makes it possible to generate patient-specific induced pluripotent stem cells (IPSCs) and induce pluripotent stem cells to differentiate into cholinergic neurons. In 2006, Dr Yamanaka's group developed a novel procedure to induce mouse embryonic and adult fibroblasts to dedifferentiate into IPSCs using 4 transcriptional factors, Oct4, Sox2, and Klf4 . Later on, more and more groups use similar strategies to get IPSCs from somatic cells of normal people, even some patients     . This breakthrough makes Dr. Yamanaka to share the Nobel Prize in Physiology or Medicine in 2012 with Dr. Gurdon. Here, I will talk about the recent progress of modeling and therapeutic studies of AD using pluripotent stem cells, including IPSCs and embryonic stem cells (ESCs). Modeling AD using Pluripotent Stem Cells IPSCs derived from somatic cells of patients allow us to study the effects of genetic changes on the developmental and pathological changes of diseases. Yagi et al.  firstly generated IPSCs from familial AD (FAD) patients carrying PS1 and PS2 mutations and induced FAD-IPSCs to differentiate into neurons. In this study, they found that neurons derived from FAD-IPSCs carrying PS1 and PS2 mutations have increased amyloid β42 secretion. This phenomenon has been found in patients' brain with PS mutations. After applied ɣ-secretase inhibitor, Compound E, amyloid β42 secretion decreased  . In 2012, Israel et al. generated IPSCs from two AD patients carrying the duplication of the Aβ precursor protein gene (APP Dp ). They found that levels of Aβ40, phospho-tau and active glycogen synthase kinase-3β (aGSK-3β) were higher in IPSC-derived neurons from patients carrying APP Dp mutation than that of controls. Interestingly, similar phenomena were observed in IPSC-derived neurons from sporadic AD patients. They also found that the genome of IPSC-derived neurons from one of sporadic AD patients had similar phenotypes with FAD samples  . Kondo et al.  generated IPSCs from FAD patients carrying E693∆ mutation and sporadic AD and induced IPSCs to differentiate into cortical neurons. The level of Aβ oligomers in IPSC-derived neurons and astrocytes carrying E693∆ mutation increased. The accumulated Aβ oligomers caused endoplasmic reticulum and oxidative stress, which could be reversed after applied docosahexaenoic acid (DHA)  . Cortical neurons were also generated from Down syndrome-IPSCs (DS-IPSCs) and ESCs (DS-ESCs). Cortical neurons derived from DS-IPSCs showed that extracellular accumulation of pathogenic Aβ42 in the culture of cortical neurons derived from DS-IPSCs is much higher than that of control in the late stage (after day 70). BTA1-labeled amyloid showed that intracellular and extracellular aggregates of amyloid in DS-IPSCderived cortical neurons. To verify this observation, they generated cortical neurons from DS-ESCs. Extracellular and intracellular Aβ42 aggregation was observed in cortical neurons derived from DS-ESCs. Furthermore, the distribution of Aβ42 aggregation in cortical neurons derived from DS-ESCs was similar with that in cortical neurons derived from DS-IPSCs. These studies illustrated that IPSC-derived neurons from AD patients can be used to analyze pathological changes and screen the drugs for clinical applications  .