A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer's disease.
Agonists of the peroxisome proliferator activated receptor gamma (PPARgamma) have been shown to reduce inflammatory responses in several animal models of neurological diseases and conditions and to reduce amyloid burden in transgenic mice expressing mutant forms of human amyloid precursor protein. However, the effects of activating the related receptor PPARdelta (PPARdelta), which is expressed at higher levels in the brain than PPARgamma, on inflammation and amyloid burden have not been explored. In this study we tested the effects of the selective PPARdelta agonist GW742 in 5xFAD mice which harbor 3 mutations in amyloid precursor protein and 2 mutations in presenilin 1, develop plaques by 5-6 weeks of age, and show robust inflammation and neuronal damage. Oral delivery of GW742 significantly reduced amyloid plaque burden in the subiculum region of 3-month old male and female 5xFAD mice. GW742 also significantly reduced astrocyte activation, suggesting anti-inflammatory effects on glia cells. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme, while in transfected HEK293 cells, GW742 activated a neprilysin promoter driving luciferase expression. These results suggest that, as found for some PPARgamma agonists, PPARdelta agonists can also reduce amyloid burden likely to be mediated by effects on amyloid clearance.
Kalinin
Sergey
S
Department of Anethesiology, University of Illinois, & Jesse Brown Veterans Affairs Hospital, Chicago, IL 60612, USA.
Richardson
Jill C
JC
Feinstein
Douglas L
DL
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015260:Neprilysin / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C464800:GW 742; D047494:PPAR delta; D053764:Presenilin-1; D013844:Thiazoles; D015260:Neprilysin