Introduction: Alzheimer's disease (AD) is a neurodegenerative disease responsible for 60–70% of the 50 million cases of dementia worldwide. It is caused by synaptic failure and excessive accumulation of misfolded proteins. This disease is associated with complications such as neurodegeneration, shrinking of brain tissue, and progressive cognitive, motor, and behavioral disorders which often are fatal. Some failures and ambiguous results of anti-tau and anti-inflammatory treatments and significant progression in the field of cell therapy have inclined the scientific community to new methods such as stem cell therapy. In recent years, with the improvement and maturity of induced pluripotent stem cell technology and direct cell reprogramming technology, the differentiation of human somatic cells followed by their transformation into nerve cells has become possible in vitro and in vivo. Induced pluripotent stem cells (iPSCs) are utilized in two procedures for discovering new therapeutic approaches for neurodegenerative diseases, including Alzheimer's. iPSC-derived cells can be implanted directly to regenerate neuronal subtypes or be used to fabricate constructs for drug testing and AD modeling. In this review, we will discuss the importance of Alzheimer's disease-induced pluripotent stem cell models in analyzing PSEN1 gene mutations’ implications over the early stages of Alzheimer's disease pathogenesis throughout neuronal differentiation impairment.
Methods: In the context of these modelings, researchers generated human iPSCs from fibroblasts from a patient with AD harboring a specific mutation in the PSEN1 gene and reprogrammed the cells using viral vectors. iPSCs exhibited the ability to differentiate into neuronal lineage in a 3D environment. These iPSC-derived neurons harbored Aβ oligomers confirmed by Western Blot (WB) and immunostaining
Results: Taking into account that the disturbance in the regulation of neural miRNA may play a role in the pathophysiology of Alzheimer's disease (AD), researchers utilized the neurons derived from iPSCs mutated in the PSEN1 gene. Although miR-124 function may be dependent on the neuronal AD model, data indicate that keeping the miR-124 level strictly controlled is crucial for proper neuronal function. Furthermore, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies. In another recent study, the potential of the iPSC-based familial AD cell model was evaluated as a platform for drug testing. NPS 2143, a negative allosteric modulator of the calcium-sensing receptor, was used as a potential drug for AD treatment. Maria Lo Giudice et al, in their studies, assessed the potential of their iPSCs-based familial AD cellular model as a platform for drug testing. They found that iPSCs-derived neurons respond to treatment with ү-secretase inhibitor, modifying the physiological amyloid-β protein precursor (AβPP) processing and amyloid-β (Aβ) secretion. Moreover, they demonstrated the expression of calcium sensing receptor (CaSR) protein in human neurons derived from healthy and familial AD subjects. Recently, researchers have looked for the effect of some mutations such as L286V and R278I on PSEN1 gene function, and in this regard, the control and mutation of PSEN1 and the spontaneous differentiation of human neural stem cells into neuron and astrocyte co-cultures were investigated. paper data provides evidence that the PSEN1 mutations L286V and R2781 significantly alter protein expression associated with AβPP processing and cellular redox status, and that study highlights the potential for iPSC-derived neuron and astrocyte co-cultures to be used as an early human model of FAD. Another research indicates that presenilin-1 plays an essential role in neural progenitor maintenance, neurogenesis, neurite outgrowth, synaptic function, neuronal function, myelination, and plasticity. Therefore, an imbalance caused by mutations in presenilin-1/ү-secretase might cause aberrant signaling, synaptic dysfunction, memory impairment, and increased Aβ42/Aβ40 ratio, contributing to neurodegeneration during the initial stages of AD pathogenesis.
Conclusion: iPSCs-based models from AD have and will play a significant role in analyzing mutations, studying the Alzheimer's disease progression process, and screening molecules. iPSCs-based models are very efficient in the study of PSEN1 gene mutations and the physiological processing of protein Aβ, and due to the mentioned links between these two with AD, they could be promising in advancing therapeutic strategies.