A novel presenilin 1 nucleotide mutation (M139I) and its pathological function in a Chinese family with early-onset Alzheimer’s disease

BackgroundThe majority of early-onset familial Alzheimer's disease is caused by mutations in the presenilin 1 (<i>PSEN1</i>) gene.ObjectiveTo investigate the pathogenic mechanism of the novel nucleotide mutations of the <i>PSEN1</i> gene in early-onset familial Alzheimer's disease.MethodsWe describe a Chinese family with autosomal dominant early-onset Alzheimer's disease. Gene sequencing revealed that the 417th nucleotide in the exon 5 of the <i>PSEN1</i> gene had changed from G to C. This resulted in methionine being substituted by isoleucine at codon 139. To support that the novel mutation was pathological, we transfected lentiviruses that overexpressed wild-type and mutant <i>PSEN1</i> gene sequences into SH-SY5Y cells to construct a cell model.ResultsThe present study showed that the <i>PSEN1</i> M139I mutation led to an increase in the Aβ₄₂/Aβ₄₀ ratio. In addition, this mutation induced the expression of β-site APP-cleaving enzyme 1 (BACE-1). Analysis of the steady-state mechanism showed that the <i>PSEN1</i> M139I mutation cells were more susceptible to endoplasmic reticulum stress and apoptosis under hydrogen peroxide induction than the wild type cells were.ConclusionsIn this study, we demonstrate that the <i>PSEN1</i> M139I nucleotide mutation a new mutation that, can increase the ratio of intracellular Aβ₄₂ and Aβ₄₂/Aβ_40, and increase endoplasmic reticulum stress to promote apoptosis. This supports that the <i>PSEN1</i> M139I mutation is a pathological mutation.