Endoplasmic reticulum stress induces Alzheimer disease‐like phenotypes in the neuron derived from the induced pluripotent stem cell with D678H mutation on amyloid precursor protein

Alzheimer disease (AD), a progressive neurodegenerative disorder, is mainly caused by the interaction of genetic and environmental factors. The impact of environmental factors on the genetic mutation in the amyloid precursor protein (APP) is not well characterized. We hypothesized that endoplasmic reticulum (ER) stress would promote disease for the patient carrying the APP D678H mutation. Therefore, we analyzed the impact of a familial AD mutation on amyloid precursor protein (APP D678H) under ER stress. Induced pluripotent stem cells (iPSCs) from APP D678H mutant carrier was differentiated into neurons, which were then analyzed for AD‐like changes. Immunocytochemistry and whole‐cell patch‐clamp recording revealed that the derived neurons on day 28 after differentiation showed neuronal markers and electrophysiological properties similar to those of mature neurons. However, the APP D678H mutant neurons did not have significant alterations in the levels of amyloid‐β (Aβ) and phosphorylated tau (pTau) compared to its isogenic wild‐type neurons. Only under ER stress, the neurons with the APP D678H mutation had more Aβ and pTau via immune detection assays. The higher level of Aβ in the APP D678H mutant neurons was probably due to the increased level of β‐site APP cleaving enzyme (BACE1) and decreased level of Aβ‐degrading enzymes under ER stress. Increased Aβ and pTau under ER stress reduced the N‐methyl‐D‐aspartate receptor (NMDAR) in Western blot analysis and altered electrophysiological properties in the mutant neurons. Our study provides evidence that the interaction between genetic mutation and ER stress would induce AD‐like changes. Cover Image for this issue: https://doi.org/10.1111/jnc.15420 Alzheimer's disease (AD) is caused by the combination of genetic and environmental factors. Here, we use iPSC‐derived neurons to study the impact of ER stress on the AD‐like phenotypes. Under ER stress, the APP D678H mutant (M) neurons have higher Aβ producing enzyme BACE1 and lower Aβ‐degrading enzymes, and thus have more Aβ than isogenic wild‐type (WT) neurons. Furthermore, M neurons have more insoluble phosphorylated Tau and less NR1 than WT neurons. These changes may lead to electrophysiological impairments in M neurons. Therefore, our study provides the evidence to maintain a healthier lifestyle to delay AD onset. Cover Image for this issue: https://doi.org/10.1111/jnc.15420