Extracellular aggregates of amyloid-β peptides (Aβ) are a hallmark in Alzheimer's disease (AD) brains. Recent findings suggest that Aβ is generated intracellularly and potential production sites include endosomes and trans-Golgi network. We determined the production of Aβ in subcellular fractions isolated from mouse brain.
View Article and Find Full Text PDFIt is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation.
View Article and Find Full Text PDFThe apolipoprotein E (APOE) gene remains the most strongly established risk factor for late onset Alzheimer's disease (LOAD). Recently the gene, TOMM40, which is in linkage disequilibrium with APOE, was identified to be associated with LOAD in genome-wide association studies. One of the identified polymorphisms in TOMM40 is rs10524523, which is located in intron 6 and composed of thymidine repeats varying between 14 to 36 base-pairs in length.
View Article and Find Full Text PDFSignificance: Detailed knowledge about cell death and cell survival mechanisms and how these pathways are impaired in neurodegenerative disorders and cancer forms the basis for future drug development for these diseases that affect millions of people around the world.
Recent Advances: In neurodegenerative disorders such as Alzheimer's disease (AD), cell death pathways are inappropriately activated, resulting in neuronal cell death. In contrast, cancer cells develop resistance to apoptosis by regulating anti-apoptotic proteins signaling via mitochondria.
Markers for caspase activation and apoptosis have been shown in brains of Alzheimer's disease (AD) patients and AD-mouse models. In neurons, caspase activation is associated with elevated amyloid β-peptide (Aβ) production. Caspases cleave numerous substrates including presenilin-1 (PS1).
View Article and Find Full Text PDFDimebon, a drug currently being evaluated in multiple Phase III Alzheimer's disease trials, has previously been shown to have effects on isolated mitochondria at muM concentrations. Here the effects of nM concentrations of Dimebon on mitochondrial function were investigated both in primary mouse cortical neurons and human neuroblastoma cells (SH-SY5Y). Under non-stress conditions nM concentrations of Dimebon increased succinate dehydrogenase activity (MTT-assay), mitochondrial membrane potential (DeltaPsim), and cellular ATP levels.
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