English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Many cases of autosomal dominant early onset Alzheimer’s disease (AD) result from mutations in the gene encoding presenilin-1 (PS-1). PS-1 is an integral membrane protein expressed ubiquitously in neurons throughout the brain in which it is located primarily in endoplasmic reticulum (ER). Although the pathogenic mechanism of PS-1 mutations is unknown, recent findings suggest that PS mutations render neurons vulnerable to apoptosis. Because increasing evidence indicates that mitochondrial alterations contribute to neuronal death in AD, we tested the hypothesis that PS-1 mutations sensitize neurons to mitochondrial failure. PC12 cell lines expressing a PS-1 mutation (L286V) exhibited increased sensitivity to apoptosis induced by 3-nitropropionic acid (3-NP) and malonate, inhibitors of succinate dehydrogenase, compared with control cell lines and lines overexpressing wild-type PS-1. The apoptosis-enhancing action of mutant PS-1 was prevented by antioxidants (propyl gallate and glutathione), zVAD-fmk, and cyclosporin A, indicating requirements of reactive oxygen species (ROS), caspases, and mitochondrial permeability transition in the cell death process. 3-NP induced a rapid elevation of [Ca2+]i, which was followed by caspase activation, accumulation of ROS, and decreases in mitochondrial reducing potential and transmembrane potential in cells expressing mutant PS-1. The calcium chelator BAPTA AM and agents that block calcium release from ER and influx through voltage-dependent channels prevented mitochondrial ROS accumulation and membrane depolarization and apoptosis. Our data suggest that by perturbing subcellular calcium homeostasis presenilin mutations sensitize neurons to mitochondria-based forms of apoptosis that involve oxidative stress.

the journal of neuroscience/the journal of neuroscience

Increased Sensitivity to Mitochondrial Toxin-Induced Apoptosis in Neural Cells Expressing Mutant Presenilin-1 Is Linked to Perturbed Calcium Homeostasis and Enhanced Oxyradical Production