PPAR[gamma] Recruitment to Active ERK during Memory Consolidation Is Required for Alzheimer's Disease-Related Cognitive Enhancement

• Published in: The Journal of neuroscience 2014-03, Vol.34 (11), p.4054-4063
• Main Authors: Jahrling, Jordan B, Hernandez, Caterina M, Denner, Larry, Dineley, Kelly T
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.4024-13.2014

Cognitive impairment is a quintessential feature of Alzheimer's disease (AD) and AD mouse models. The peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) agonist rosiglitazone improves hippocampus-dependent cognitive deficits in some AD patients and ameliorates deficits in the Tg2576 mouse model for AD amyloidosis. Tg2576 cognitive enhancement occurs through the induction of a gene and protein expression profile reflecting convergence of the PPAR[gamma] signaling axis and the extracellular signal-regulated protein kinase (ERK) cascade, a critical mediator of memory consolidation. We therefore tested whether PPAR[gamma] and ERK associated in protein complexes that subserve cognitive enhancement through PPAR[gamma] agonism. Coimmunoprecipitation of hippocampal extracts revealed that PPAR[gamma] and activated, phosphorylated ERK (pERK) associated in Tg2576 in vivo, and that PPAR[gamma] agonism facilitated recruitment of PPAR[gamma] to pERK during memory consolidation. Furthermore, the amount of PPAR[gamma] recruited to pERK correlated with the cognitive reserve in humans with AD and in Tg2576. Our findings implicate a previously unidentified PPAR[gamma]-pERK complex that provides a molecular mechanism for the convergence of these pathways during cognitive enhancement, thereby offering new targets for therapeutic development in AD.