ABSTRACT
Fundamental changes in the composition and distribution of lipids within the brain are believed to contribute to the cognitive decline associated with Alzheimer's disease (AD). The mechanisms by which these changes in lipid composition affect cellular function and ultimately cognition are not well understood. Although "candidate gene" approaches can provide insight into the effects of dysregulated lipid metabolism they require a preexisting understanding of the molecular targets of individual lipid species. In this report we combine unbiased gene expression profiling with a genome-wide chemogenomic screen to identify the mitochondria as an important downstream target of PC(O-16:0/2:0), a neurotoxic lipid species elevated in AD. Further examination revealed that PC(O-16:0/2:0) similarly promotes a global increase in ceramide accumulation in human neurons which was associated with mitochondrial-derived reactive oxygen species (ROS) and toxicity. These findings suggest that PC(O-16:0/2:0)-dependent mitochondrial dysfunction may be an underlying contributing factor to the ROS production associated with AD.
Subject(s)
Alzheimer Disease/metabolism , Lipid Metabolism , Mitochondria/metabolism , Signal Transduction , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Cell Line , Cells, Cultured , Ceramides/metabolism , Gene Expression Profiling , Humans , Lipid Metabolism/genetics , Mechanistic Target of Rapamycin Complex 2 , Membrane Potential, Mitochondrial , Mitochondria/genetics , Multiprotein Complexes/metabolism , Neurons/metabolism , Open Reading Frames , Oxidative Stress , Reactive Oxygen Species/metabolism , TOR Serine-Threonine Kinases/metabolismABSTRACT
Perturbation of lipid second messenger networks is associated with the impairment of synaptic function in Alzheimer disease. Underlying molecular mechanisms are unclear. Here, we used an unbiased lipidomic approach to profile alkylacylglycerophosphocholine second messengers in diseased tissue. We found that specific isoforms defined by a palmitic acid (16:0) at the sn-1 position, namely 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) and 1-O-hexadecyl-sn-glycero-3-phosphocholine (C16:0 lyso-PAF), were elevated in the temporal cortex of Alzheimer disease patients, transgenic mice expressing human familial disease-mutant amyloid precursor protein, and human neurons directly exposed to amyloid-beta(42) oligomers. Acute intraneuronal accumulation of C16:0 PAF but not C16:0 lyso-PAF initiated cyclin-dependent kinase 5-mediated hyperphosphorylation of tau on Alzheimer disease-specific epitopes. Chronic elevation caused a caspase 2 and 3/7-dependent cascade resulting in neuronal death. Pharmacological inhibition of C16:0 PAF signaling, or molecular strategies increasing hydrolysis of C16:0 PAF to C16:0 lyso-PAF, protected human neurons from amyloid-beta(42) toxicity. Together, these data provide mechanistic insight into how disruptions in lipid metabolism can determine neuronal response to accumulating oligomeric amyloid-beta(42).
Subject(s)
Amyloid beta-Peptides/metabolism , Neurons/metabolism , Neurons/pathology , Peptide Fragments/metabolism , Phosphatidylcholines/metabolism , Signal Transduction , tau Proteins/metabolism , Aged , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/toxicity , Animals , Calpain/metabolism , Caspases/metabolism , Cell Survival/drug effects , Cytoprotection/drug effects , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/enzymology , Endoplasmic Reticulum/pathology , Enzyme Activation/drug effects , Epitopes/immunology , Glycogen Synthase Kinase 3/metabolism , Humans , Intracellular Space/drug effects , Intracellular Space/metabolism , Mice , Mice, Transgenic , Peptide Fragments/chemistry , Peptide Fragments/toxicity , Phospholipid Ethers/metabolism , Phosphorylation/drug effects , Protein Structure, Quaternary , Signal Transduction/drug effects , Stress, Physiological/drug effectsABSTRACT
Inhibitors of HIV protease have been shown to have antiapoptotic effects in vitro, yet whether these effects are seen in vivo remains controversial. In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis. In mice with Fas-induced fatal hepatitis, Staphylococcal enterotoxin B-induced shock, and middle cerebral artery occlusion-induced stroke, we demonstrate that PIs significantly reduce apoptosis and improve histology, function, and/or behavioral recovery in each of these models. Further, we demonstrate that both in vitro and in vivo, PIs block apoptosis through the preservation of mitochondrial integrity and that in vitro PIs act to prevent pore function of the adenine nucleotide translocator (ANT) subunit of the mitochondrial permeability transition pore complex.
