Aging-Related and Gender Specific Albumin Misfolding in Alzheimer’s Disease

摘要

Aging-related protein misfolding and aggregation may play critical roles in the pathogenesis of numerous diseases. In the brain, extracellular aggregated amyloid-β (Aβ) is closely related to the death of neurons in individuals with Alzheimer’s disease (AD). Albumin-Aβ binding is important in preventing Aβ fibril aggregation. However, because albumin is the most abundant and important antioxidant in the circulation, aging-related oxidative stress could have a significant effect on the molecular conformation and binding capacities of albumin. To investigate the link between misfolded albumin and AD, we developed fluorescent assays to determine the effects of misfolded albumin on membrane integrity in the presence of a lipolytic, inflammatory response-like enzyme, secretory phospholipase A2 (sPLA2). We found that misfolded albumin increased degradation of phospholipids in highly fluid bilayer membranes in the presence of sPLA2 due to hydrophobic effects of misfolded albumin. High amounts of misfolded albumin were present in sera of elderly (average 74 years) versus young (average 24 years) subjects (  p p = 0.0006). This study suggests that inflammation, misfolded albumin and/or other dysfunctional proteins, and changes in membrane fluidity could alter cell membrane integrity and homeostasis and contribute to the pathogenesis of aging-related dementia and AD.