Pathological SORLA protein variant in Alzheimer's disease development



Year of publication 2022
Type Conference abstract
Description Alzheimer’s disease (AD) is a degenerative brain disease manifested by progressive memory loss with pathological hallmarks: amyloid-ß plaques and Tau neurofibrillary tangles. More than 55 million people are affected worldwide, rising by ten million each year [1]. Although most AD cases are sporadic and presumably triggered by the interplay of genetic and environmental factors, several mutations in specific genes (APP, PSEN1, PSEN2) lead to the early-onset variant of AD. Recently, genetic variants in the SORL1 gene (encoding SORLA protein) were associated with AD development. Therefore SORL1 is considered the “fourth” AD gene [2]. SORLA is an intracellular sorting receptor, shuttling its cargo between the trans-Golgi network and early endosomes. SORLA directly regulates amyloid precursor protein (APP) recycling and maintains amyloid-ß processing [3]. Polymorphisms in SORL1 affect the imbalance of the ß-amyloid levels, but the detailed molecular mechanism in SORLA-dependent AD development remains unclear. The goal of this project was to develop stem cell-based model with SORLA pathogenic mutation and use it to study the effect of this mutation on the biology of neurons. Specifically, we introduced mutation (G1732A) in the SORL1 gene by using CRISPR/Cas9 technology into induced pluripotent stem cells (iPSCs) and adapted in vitro model of inducible neurons for AD modeling [4]. We prepared fully differentiated neurons and collected samples at different timepoints to assess the dynamics of this process. Subsequently, we determined several parameters, including APP protein level and endosomal swelling. Our results show that the pathogenic protein SORLA does significantly affect AD progression. In conclusion, we show that iPSCs are relevant in vitro models of AD. [1] W. H. Organization, “Global action plan on the public health response to dementia 2017 - 2025,” Geneva World Heal. Organ., p. 52, 2017, [Online]. Available: [2] S. Mishra et al., “The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons,” Cell. Mol. Life Sci., vol. 79, no. 3, 2022, doi: 10.1007/s00018-022-04182-9. [3] O. M. Andersen et al., “Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein,” Proc. Natl. Acad. Sci. U. S. A., vol. 102, no. 38, pp. 13461–13466, 2005, doi: 10.1073/pnas.0503689102. [4] M. S. Fernandopulle, R. Prestil, C. Grunseich, C. Wang, L. Gan, and M. E. Ward, “Transcription Factor–Mediated Differentiation of Human iPSCs into Neurons,” Curr. Protoc. Cell Biol., vol. 79, no. 1, pp. 1–48, 2018, doi: 10.1002/cpcb.51.

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