Biochim Biophys Acta; co-auth.: L.Michalik, W.Wahli

Biochim Biophys Acta. 2013 Mar 15. pii: S0925-4439(13)00080-X. doi: 10.1016/j.bbadis.2013.03.006. [Epub ahead of print]

Tau hyperphosphorylation and increased bace1 and rage levels in the cortex of PPARβ/δ-null mice.


Unitat de Farmacologia, Department de Farmacologia i Química Terapèutica, Facultat de Farmàcia, Universitat de Barcelona, Institut de Biomedicina de la UB (IBUB); Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM), Spain.


The role of peroxisome proliferator activator receptor (PPAR)β/δ in the pathogenesis of Alzheimer’s disease has only recently been explored through the use of PPARβ/δ agonists. Here we evaluated the effects of PPARβ/δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation. PPARβ/δ-null mice showed cognitive impairment in the object recognition task, accompanied by enhanced DNA-binding activity of NF-κB in the cortex and increased expression of IL-6. In addition, two NF-κB-target genes involved in β-amyloid (Aβ) synthesis and deposition, the β site APP cleaving enzyme 1 (Bace1) and the receptor for advanced glycation endproducts (Rage), respectively, increased in PPARβ/δ-null mice compared to wild-type animals. The protein levels of glial fibrillary acidic protein (GFAP) increased in the cortex of PPARβ/δ-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 PPARβ/δ-/- mice. Collectively, our findings indicate that PPARβ/δ deficiency results in cognitive impairment associated with enhanced inflammation, astrogliosis and tau hyperphosphorylation in the cortex.

Copyright © 2013. Published by Elsevier B.V.