Aging-related protein misfolding and aggregation may play critical roles in the pathogenesis of numerous diseases. In the brain, extracellular aggregated amyloid-␤ (A␤) is closely related to the death of neurons in individuals with Alzheimer's disease (AD). Albumin-A␤ binding is important in preventing A␤ 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 < 0.0001). Albumin in cerebrospinal fluid (CSF) of elderly subjects, though present in small concentrations, had a 2-to 3-fold increased capacity to promote sPLA2-catalyzed membrane phospholipid degradation as compared with the same amount of albumin in serum (p < 0.0001). In addition, the fatty acid binding capacity of albumin in CSF from female subjects was considerably lower than values obtained for men, especially for individuals diagnosed with AD (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.

Because oxygen tension can be extremely low in respiratory secretions of patients with cystic fibrosis (CF), host inflammatory cells in the airspace milieu may resort to anaerobic metabolism with production of lactic acid under hypoxic conditions. We found elevated lactate levels in bronchoalveolar lavage (BAL) fluid specimens obtained from patients with CF, and lactate concentrations correlated with neutrophil and neutrophil-derived mediator concentrations. We suggest that neutrophils, particularly when present in high numbers, may resort to anaerobic metabolism due to hypoxia in CF respiratory secretions and generate lactate, which may be a useful biomarker of inflammation in the CF lung.

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