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- W2896071760 abstract "Heterozygous mutations in Presenilin 2 (PSEN2) cause nearly fully penetrant autosomal dominant Alzheimer Disease (AD). PSEN2, an essential component of the gamma-secretase complex of proteins, catalyzes a crucial step in the amyloidogenic amyloid precursor protein (APP) cleavage cascade to generate amyloid-beta (Aβ) peptides. Accumulation of aberrantly-produced insoluble Aβ isoforms is an important component of AD pathogenesis. While most driver PSEN2 mutations are missense, we have discovered a novel heterozygous PSEN2 two-basepair deletion frameshift mutation (PSEN2K115fsX) in two unrelated individuals with AD. To determine whether this mutation exhibits molecular hallmarks of AD, we generated induced pluripotent stem cells (iPSCs) from patient fibroblasts to study cell type-specific mutational effects. Following differentiation of control and mutant iPSCs into cortical neurons, we measured secreted Aβ isoforms in conditioned media and found that the ratio of insoluble to soluble Aβ is increased from mutant cells. To validate this PSEN2 mutation as a molecular driver of these observations, we are testing whether correction of the mutation in genome-edited isogenic iPSC lines rescues the Aβ phenotype. This frameshift mutation offers a unique way to probe the impact of major biochemical changes to the expression and function of one PSEN2 allele. We are analyzing the impact of mutation on PSEN2 RNA splice isoforms as well as exploring the greater role of PSEN2 AD mutations in human microglia through iPSC differentiation." @default.
- W2896071760 created "2018-10-26" @default.
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- W2896071760 date "2018-07-01" @default.
- W2896071760 modified "2023-10-16" @default.
- W2896071760 title "P3‐162: IPSC‐DERIVED CORTICAL NEURONS WITH A NOVEL FRAMESHIFT PSEN2 MUTATION INCREASE THE RATIO OF AGGREGATE PRONE AMYLOID BETA" @default.
- W2896071760 doi "https://doi.org/10.1016/j.jalz.2018.06.1520" @default.
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