Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles, and is accompanied by a robust inflammatory response that clinically presents as the progressive loss of cognition and memory, ultimately leading to death. The disease is associated with a disruption of Aβ homeostasis and it’s deposition in the brain, which initiates a microglial-mediated immune response that produces pro-inflammatory cytokines and reactive nitrogen and oxygen species.
Using ibuprofen, a peroxisome proliferator activated receptor γ (PPARγ) agonist and non-steroidal anti-inflammatory (NSAID), we demonstrate that chronic ibuprofen treatment reduces Aβ burden by 90% in the parenchyma and prevents microglia, the primary producers of reactive oxygen and nitrogen species, from forming the NADPH oxidase. Ibuprofen prevents the phosphorylation of Vav and consequently RAC1 translocation to the plasma membrane, preventing NADPH oxidase assembly, thus inhibiting the release of superoxide radicals. Consequently, we report less oxidative damage in the brains of mice treated with ibuprofen.
We further extend our studies to assess the mechanism of Aβ removal from the brain and the behavioral outcomes in mouse models of AD, by using a retinoid X receptor (RXR) selective, FDA approved agonist, bexarotene. We show that bexarotene utilizes its ability and obligation to heterodimerize with Liver X Receptor (LXR) to induce the expression of LXR response element genes, apolipoprotein E, ABCA1 and ABCG1, and elevating HDL levels in the brains of treated AD mice. We show that following 1 dose of bexarotene, soluble Aβ levels are reduced for up to 84 hours. We show that after just 72 hours of bexarotene treatment, the plaque burden is reduced by 50%. The consequence of reducing soluble Aβ levels is correlative to ameliorating the AD-related behavioral deficits in three different AD mouse models and reversing a neural circuit deficit.
Together our data demonstrate the important roles for nuclear receptors in preventing the inflammation associated with AD and facilitating clearance of Aβ species. These data may provide a novel therapeutic strategy for the treatment of the neurodegenerative disease and its prodromal states.