Enhancement of select cognitive domains with rosiglitazone implicates dorsal hippocampus circuitry sensitive to PPARγ agonism in an Alzheimer's mouse model

INTRODUCTION: Several clinical studies have tested the efficacy of insulin‐sensitizing drugs for cognitive enhancement in Alzheimer's disease (AD) patients, as type 2 diabetes (T2D) is a well‐recognized risk factor for AD. Pilot studies assessing FDA‐approved diabetes drugs in subjects with early‐stage disease have found cognitive benefit in subjects comorbid for insulin resistance. In AD mouse models with concomitant insulin resistance, we have shown that 4 weeks of RSG can reverse peripheral and central insulin resistance concomitant with rescue of hippocampus‐dependent fear learning and memory and hippocampal circuitry deficits in 9‐month‐old (9MO) Tg2576 mice with no effect in wild‐type (WT) mice. Bioinformatics analysis of genomic and proteomic data reveals an intimate link between PPARγ and MAPK/ERK signaling in the hippocampus. We then demonstrated a direct interaction between PPARγ and phospho‐ERK in vitro and in vivo during memory consolidation. The translational value of this discovery is evidenced by the positive correlational relationship between human AD postmortem brain levels of pERK‐PPARγ nuclear complexes with cognitive reserve. METHODS: We tested whether insulin sensitizer therapy could rescue spatial navigation, context discrimination, and object recognition learning and memory in aged wild‐type and Tg2576 mice in addition to hippocampus‐dependent contextual fear learning and memory, as we have previously reported. RESULTS: We found that rosiglitazone treatment improved cognitive domains that predominantly rely upon the dorsal hippocampus rather than those that additionally engage the ventral hippocampus. CONCLUSION: These results suggest that insulin sensitizer therapy with rosiglitazone improved age‐ and AD‐related learning and memory deficits in circuit selective ways.