Inflammation and neurodegeneration: identification of the acute phase protein haptoglobin as a potential modulator of apolipoprotein E-mediated regulation of brain cholesterol and beta-amyloid homeostasis

State of the art: Alterations in cholesterol metabolism play a role in the pathogenesis of neurodegenerative diseases. Apolipoprotein E, the main lipid carrier in the brain, is a risk factor for Alzheimer’s disease. How brain cholesterol homeostasis may be related to Apolipoprotein E as a risk factor needs further clarification. A strategy might be to focus on factors that may modulate the Apolipoprotein E function. In this frame, we obtained experimental evidences that the acute-phase protein Haptoglobin binds Apolipoprotein E. Objectives and Rationale: Haptoglobin was found in cerebral spinal fluid and suggested as a marker of blood-brain barrier dysfunction. Our main goal is to study whether Haptoglobin, because of its binding with Apolipoprotein E, might influence the apolipoprotein function in cholesterol and beta-amyloid metabolism. Experimental plan: The Hpt effect on Apolipoprotein E activity in beta-amyloid aggregation or clearance, and on the Apolipoprotein E-stimulated cholesterol incorporation or efflux from neurons, astrocytes and microglia will be evaluated. Peptides or molecules able to influence the Haptoglobin binding to Apolipoprotein E will be screened. The Haptoglobin/Apolipoprotein E ratio will be evaluated in AD patients, as a potential diagnostic marker to monitor disease activity or the efficiency of a treatment. Expected results and their relevance: The Haptoglobin influence on Apolipoprotein E key roles in brain will be elucidated. Modulators of the Haptoglobin-Apolipoprotein E interaction are expected to be identified. The results of this study might provide new tools to set up diagnostic methods, or design molecules for therapeutic approaches in disease treatment.