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

Abstract

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.

The Citrus Flavonoid Hesperetin Encounters Diabetes-Mediated Alzheimer-Type Neuropathologic Changes through Relieving Advanced Glycation End-Products Inducing Endoplasmic Reticulum Stress

“…Evidence confirms that rosiglitazone protects the cell against oxidative stress, inflammation, and apoptosis, and lessens AGE-induced damage in neural stem cells [13]. In in vivo models of AD, rosiglitazone significantly improved memory and cognition deficits; these beneficial effects were observed in AD patients as well [14,15]. Thus, anti-diabetic drugs could be positive in treating AD.…”

Alzheimer’s Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment

“…In behavioral tests, these mice also exhibited learning and memory impairments in spatial reference and alternation tasks at 9–10 months of age, although no significant differences were found at 3 months of age [ 70 ]. Additionally, Tg2576 mice exhibit learning- and memory-associated abnormalities in the T-maze alternation task [ 72 ] and hippocampus-dependent fear memory [ 72 , 73 ] and amygdala-dependent cued fear learning ability in the FC test [ 74 ], suggesting that these mice have a widespread deficit in cognitive functions. The behavioral and pathological features of Tg2576 mice resemble those observed in human AD.…”

“…However, ibuprofen has both positive [ 189 ] and negative effects [ 190 ] in clinical trials. The peroxisome proliferator-activated receptor γ agonists rosiglitazone and pioglitazone also ameliorate hippocampus-dependent memory impairment in Tg2576 mice [ 73 , 191 ], APP/PS1 mice [ 192 ], and 3×Tg-AD mice [ 193 ], but the results from clinical trials were not consistent with those from the animal experiments [ 194 , 195 , 196 , 197 ]. Multiple AD clinical trials using statin drugs, which decrease blood cholesterol, were performed.…”