Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARβ/δ-null mice

The role of peroxisome proliferator activator receptor (PPAR)beta/delta in the pathogenesis of Alzheimer's disease has only recently been explored through the use of PPAR beta/delta agonists. Here we evaluated the effects of PPAR beta/delta deficiency on the amyloidogenic pathway and tau hyperphosphorylation. PPAR beta/delta-null mice showed cognitive impairment in the object recognition task, accompanied by enhanced DNA-binding activity of NF-kappa B in the cortex and increased expression of IL-6. In addition, two NF-kappa B-target genes involved in beta-amyloid (A beta) synthesis and deposition, the beta site APP cleaving enzyme 1 (Bace1) and the receptor for advanced glycation endproducts (Rage), respectively, increased in PPAR beta/delta-null mice compared to wild type animals. The protein levels of glial fibrillary acidic protein (GFAP) increased in the cortex of PPAR beta/delta-null mice, which would suggest the presence of astrogliosis. Finally, tau hyperphosphorylation at Ser199 and enhanced levels of PHF-tau were associated with increased levels of the tau kinases CDK5 and phospho-ERK1/2 in the cortex of PPAR beta/delta(-/-) mice. Collectively, our findings indicate that PPAR beta/delta deficiency results in cognitive impairment associated with enhanced inflammation, astrogliosis and tau hyperphosphorylation in the cortex. (C) 2013 Elsevier B.V. All rights reserved.