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

Background The majority of early-onset familial Alzheimer’s disease is caused by mutations in the presenilin 1 ( PSEN1 ) gene. Objective To investigate the pathogenic mechanism of the novel nucleotide mutations of the PSEN1 gene in early-onset familial Alzheimer's disease. Methods We 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 PSEN1 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 PSEN1 gene sequences into SH-SY5Y cells to construct a cell model. Results The present study showed that the PSEN1 M139I mutation led to an increase in the Aβ 42 /Aβ 40 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 PSEN1 M139I mutation cells were more susceptible to endoplasmic reticulum stress and apoptosis under hydrogen peroxide induction than the wild type cells were. Conclusions In this study, we demonstrate that the PSEN1 M139I nucleotide mutation a new mutation that, can increase the ratio of intracellular Aβ 42 and Aβ 42 /Aβ 40, and increase endoplasmic reticulum stress to promote apoptosis. This supports that the PSEN1 M139I mutation is a pathological mutation.