Summary: The S198P mutation accelerates folding of the amyloid precursor protein (APP), enabling mature APP to produce amyloid-beta (Aβ) peptides more rapidly than the non-mutant form. This discovery reveals a previously unrecognized mechanism by which a rare genetic change can contribute to Alzheimer’s disease.
Source: University of Chicago Medical Center
Researchers at the University of Chicago have identified a novel mechanism that helps explain how a rare APP gene variant is linked to familial Alzheimer’s disease.
Published April 2 in the Journal of Experimental Medicine, the study examines a mutation located in a portion of the APP gene that was not previously considered likely to cause disease. The findings challenge assumptions about which types of APP mutations can drive Alzheimer’s pathology.
Alzheimer’s disease, a progressive neurodegenerative disorder affecting more than 6 million people in the United States, is often associated with accumulation of Aβ peptides into extracellular plaques in the brain. These peptides arise when the larger APP protein is sequentially cleaved as it moves through cellular compartments.
Most known APP mutations linked to familial Alzheimer’s lie within or immediately adjacent to the region that encodes the Aβ peptide fragment. By contrast, the S198P variant studied here is located far from that region. Initially identified in two patients with Alzheimer’s, the S198P substitution—serine to proline at position 198—raised questions because it sits well outside the classical disease-associated exons.
“This mutation drew our attention because it is so distant from the Aβ-encoding region,” said senior author Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago. “It wasn’t clear how a change in this part of APP could influence disease processes.”
Led by Xulun Zhang, PhD, the team analyzed the effect of S198P in both cultured cells and mouse models. They observed that cells and mice expressing APP S198P had higher levels of Aβ peptides than those expressing wild-type APP. To determine why, the investigators examined the stages of APP processing that produce Aβ.
In cell-based experiments, the S198P mutation caused APP to fold more rapidly. Faster folding sped APP’s exit from the endoplasmic reticulum and transit through cellular compartments where amyloidogenic processing occurs, resulting in quicker and greater production of Aβ from mature APP than from non-mutant APP.
“Rapid folding enhances APP’s progression through the compartments where Aβ is generated, enabling faster production of the peptide,” Sisodia explained. Transgenic mice carrying S198P also developed increased Aβ plaque deposition, supporting the conclusion that this variant contributes to amyloid pathology in vivo.
Importantly, S198P is only partially penetrant; not everyone who carries the variant will develop Alzheimer’s. “This change influences risk rather than acting as an absolute determinant of disease,” Sisodia said, drawing a comparison to partially penetrant variants such as some BRCA1/2 mutations in breast cancer. Geneticists may find S198P in individuals without clinical disease, but studying such rare variants can uncover key biological mechanisms.
The discovery that a mutation outside the Aβ-coding exons can promote Aβ production highlights how much remains unknown about the genetic drivers of Alzheimer’s. “Many variants have been dismissed because they don’t fit established patterns,” Sisodia noted. “Investigating these rare changes opens new avenues to better understand the biology underlying the disease.”
While effective therapies remain under development, the study reinforces the relevance of Aβ peptides to Alzheimer’s pathogenesis. “Some have suggested that Aβ is not central to disease because of past clinical trial failures,” Sisodia said. “Our results support a role for Aβ and encourage renewed attention to how its production and deposition are regulated.”
Following this work on S198P, Sisodia and colleagues plan to revisit other rare APP variants previously considered benign to determine whether they similarly impact APP folding, trafficking, or Aβ generation. “We solved the mechanism for S198P—now we want to systematically evaluate other overlooked variants that clinical studies indicate may influence Alzheimer’s pathology,” he said.
Funding: This research, titled “An APP Ectodomain Mutation outside of the Aβ Domain promotes Aβ Production in vitro and deposition in vivo,” was supported by the Cure Alzheimer’s Fund and the JPB Foundation.
Additional authors include Can Zhang, Dmitry Prokopenko, Yingxia Liang, Sherri Y. Zhen, and Rudolph E. Tanzi of Massachusetts General Hospital, and Ian Weigle, Weinong Han, and Manish Aryal of the University of Chicago.
About this genetics and Alzheimer’s disease research news
Source: University of Chicago Medical Center
Contact: Alison Caldwell, PhD – University of Chicago Medical Center
Image: The image is in the public domain
Original Research: Closed access. “An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo” by Xulun Zhang et al., Journal of Experimental Medicine
Abstract
An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo
Familial Alzheimer’s disease (FAD)–linked mutations in the APP gene have typically been found within the Aβ-coding exons (16 and 17). The authors identified a very rare, partially penetrant single nucleotide variant, rs145081708, corresponding to the Ser198Pro substitution in exon 5.
In stably transfected cells, expression of APP S198P increases Aβ production through an unconventional mechanism: the mutation accelerates APP folding and exit from the endoplasmic reticulum. In transgenic mice coexpressing APP S198P and the FAD-linked PS1ΔE9 variant, both male and female animals showed higher steady-state Aβ levels and faster Aβ deposition than mice expressing APP and PS1ΔE9 alone.
This represents the first Alzheimer’s-linked APP mutation located outside exons 16 and 17 that promotes increased Aβ production and in vivo deposition.