Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease

Alzheimer's disease is associated with a disruption of amyloid beta (A beta) homeostasis, resulting in the accumulation and subsequent deposition of A beta peptides within the brain. The peroxisome proliferator-activated receptor-gamma (PPAR gamma)is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of A beta, and we found that the synthetic PPAR gamma agonist, pioglitazone, stimulated A beta degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1 Delta e9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble A beta levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant A beta-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPAR gamma activation facilitates amyloid clearance and supports the therapeutic utility of PPAR gamma agonists for the treatment of Alzheimer's disease.