Alzheimers disease (AD) is a neurodegenerative disorder histopathologically characterized by the deposition of extracellular amyloid (Ab) plaques and the formation of intracellular neurofibrillary tangles in the brain of affected individuals. Ab plaques are mainly composed of Ab peptides, protein fragments derived by proteolytic cleavage of the amyloid precursor protein (APP). An inflammatory component appears to contribute also to the pathogenesis of AD with activated microglia extensively associated with the Ab plaques and secreting proinflammatory cytokines. An important number of retrospective epidemiological studies have provided evidence that long-term treatment with some nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of AD, delays its onset, and slows the progression of the disease. In vitro and in vivo experiments confirmed the role of NSAIDs in blocking inflammatory processes associated with AD. Interestingly, the thiazolidinedione (TZD) drugs, agonists of the peroxisome proliferator-activated receptor gamma (PPARg), showed a similar anti-inflammatory and neuroprotective effect. Becausesome NSAIDs are agonists of PPARg, and given the evidence for a direct role of NSAIDs not only in modulating inflammation, but also in reducingamyloidogenesis, we decided to investigate a possible role of PPARg in AD. We hypothesized that PPARg expression or activation could have a directrole in APP metabolism and questioned whether the other members of the PPAR family could also have a similar role to PPARg in modulating amyloidogenesis. The first objective was to activate the endogenous PPARg or to increase the expression of all the PPAR members in the cell and analyse secreted and intracellular Ab species. As a second objective we analysed APP processing and the contribution of a-, b- and g-cleavages to the reduction in Ab levels. Thirdly, we hypothesized that Ab down-regulationcould be the result of an increased clearance rate of the peptide and studied the role of different types of proteases in the PPARg-enhanced degradation. Our results show that high levels of expression or activation of endogenous PPARg by highly specific agonists (TZD drugs) result in a dose-dependent down-regulation of the secreted andintracellular Ab pools.In contrast, overexpression of the other members of the PPAR family didnot modify Ab steady-state levels in the cell, and therefore the pathway for Ab regulation seems to be specific for the g-isotype. Moreover, the PPARg-activated pathway for Ab down-regulation is active in different cell lines of human and murine origin, including, most notably, murine primary glia and neuronal cultures.Further investigation of the PPARg-activated pathway showed that neither Ab production, nor secretion is affected upon PPARg activation. We report that levels of expression and activities of a-, b- and g-secretases are not modified under conditions of PPARg activation.Instead, we demonstrate that PPARg activates a pathway for Ab degradation in the cell. We show that PPARg-enhanced Ab-degrading activity is mediated by a metalloprotease that can be blocked by the metalloprotease inhibitor phenantroline and the peptide hormones insulin and glucagon. Analysing the known-Ab degrading enzymes we identified Insulin degrading enzyme (IDE) as the best candidate for the PPARg-enhanced Ab degradation. However, further analyses in murine neuronal cells lacking IDE revealed that the PPARg-activated pathway is IDE activity independent. In conclusion, PPARg activates an Ab clearance mechanism mediated by anunknown metalloprotease that is conserved between human and mice and ispresent in a variety of cells, including neuronal cells. Therefore, pharmacologic activation of this novel Ab degradation pathway via PPARg activation may represent a potential treatment for AD.