The PSEN1 E280G mutation leads to increased amyloid-ß43 production in induced pluripotent stem cell neurons and deposition in brain tissue.

Mutations in the presenilin 1 gene, PSEN1, which cause familial Alzheimer's disease alter the processing of amyloid precursor protein, leading to the generation of various amyloid-ß peptide species. These species differ in their potential for aggregation. Mutation-specific amyloid-ß peptide profiles may thereby influence pathogenicity and clinical heterogeneity. There is particular interest in comparing mutations with typical and atypical clinical presentations, such as E280G. We generated PSEN1 E280G mutation induced pluripotent stem cells from two patients and differentiated them into cortical neurons, along with previously reported PSEN1 M146I, PSEN1 R278I and two control lines. We assessed both the amyloid-ß peptide profiles and presenilin 1 protein maturity. We also compared amyloid-ß peptide profiles in human post-mortem brain tissue from cases with matched mutations. Amyloid-ß ratios significantly differed compared with controls and between different patients, implicating mutation-specific alterations in amyloid-ß ratios. Amyloid-ß42:40 was increased in the M146I and both E280G lines compared with controls. Amyloid-ß42:40 was not increased in the R278I line compared with controls. The amyloid-ß43:40 ratio was increased in R278I and both E280G lines compared with controls, but not in M146I cells. Distinct amyloid-ß peptide patterns were also observed in human brain tissue from individuals with these mutations, showing some similar patterns to cell line observations. Reduced presenilin 1 maturation was observed in neurons with the PSEN1 R278I and E280G mutations, but not the M146I mutation. These results suggest that mutation location can differentially alter the presenilin 1 protein and affect its autoendoproteolysis and processivity, contributing to the pathological phenotype. Investigating differences in underlying molecular mechanisms of familial Alzheimer's disease may inform our understanding of clinical heterogeneity.