PPARγ-pERK interaction restores memory consolidation in an Alzheimer’s disease model


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Cognitive impairment is a quintessential feature of Alzheimer’s disease (AD) and AD mouse models. We and others have previously reported the peroxisome-proliferator activated receptor gamma (PPARγ) agonist rosiglitazone improves hippocampus-dependent cognitive deficits in some AD patients and ameliorates deficits in the Tg2576 mouse model for AD amyloidosis. Since extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERK MAPK) is required for many forms of learning and memory that are affected in AD, and since both PPARγ and ERK are key mediators of insulin signaling, we tested the hypothesis that RSG-mediated cognitive improvement induces a hippocampal PPARγ pattern of gene and protein expression that converges with the ERK MAPK signaling axis in Tg2576 AD mice. In the hippocampal PPARγ transcriptome, we found significant overlap between peroxisome proliferator response element-containing PPARγ target genes and ERK-regulated, cAMP response element-containing target genes. Within the Tg2576 dentate gyrus proteome, RSG induced proteins with structural, energy, biosynthesis and plasticity functions. Several of these proteins are known to be important for cognitive function and are also regulated by ERK MAPK. Given that RSG-mediated cognitive enhancement induced convergence of the PPARγ signaling axis and the ERK cascade, we next tested whether PPARγ and ERK associated in protein complexes that subserve cognitive enhancement through PPARγ agonism. Co-immunoprecipitation revealed that PPARγ and active ERK (pERK) associated in Tg2576 hippocampal extracts in vivo, and that PPARγ agonism facilitated recruitment of PPARγ to pERK during memory consolidation. Furthermore, the amount of PPARγ recruited to pERK correlated with cognitive reserve in humans with AD and in Tg2576. Thus, PPARγ represents a signaling system that is not crucial for normal cognition yet can intercede to restore neural networks compromised by AD. Our findings implicate a previously unidentified PPARγ-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.



PPARγ, Alzheimer's disease, ERK, memory consolidation, transgenic, hippocampus, protein complex