Rosiglitazone Rescues Memory Impairment in Alzheimer's Transgenic Mice: Mechanisms Involving a Reduced Amyloid and Tau Pathology

Abstract

Clinical studies suggest that agonists at peroxisome proliferator-activated receptor gamma (PPARg) may exert beneficial effects in patients with mild-to-moderate Alzheimer's disease (AD), but the mechanism for the potential therapeutic interest of this class of drugs has not yet been elucidated. Here, in mice overexpressing mutant human amyloid precursor protein, we found that chronic treatment with rosiglitazone, a high-affinity agonist at PPARg, facilitated b-amyloid peptide (Ab) clearance. Rosiglitazone not only reduced Ab burden in the brain but, importantly, almost completely removed the abundant amyloid plaques observed in the hippocampus and entorhinal cortex of 13-month-old transgenic mice. In the hippocampus, neuropil threads containing phosphorylated tau, probably corresponding to dystrophic neurites, were also decreased by the drug. Rosiglitazone switched on the activated microglial phenotype, promoting its phagocytic ability, reducing the expression of proinflammatory markers and inducing factors for alternative differentiation. The decreased amyloid pathology may account for the reduction of p-tau-containing neuropil threads and for the rescue of impaired recognition and spatial memory in the transgenic mice. This study provides further insights into the mechanisms for the beneficial effect of rosiglitazone in AD patients.

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

“…However, in AD, PPAR gamma levels (mRNA and protein) have been found to be elevated in brain tissues [59,60]. Although PPAR gamma expression is high in AD, PPAR gamma agonists have been used in AD humans and various AD animal models and have been shown to induce beneficial effects, partly due to their anti-inflammatory effects [61][62][63][64][65][66][67]. Even if the PPAR gamma agonist pioglitazone, in combination with riluzole, does not increase survival in ALS patients [54], PPAR gamma represents a useful therapeutic target in several animal models.…”

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…Pioglitazone treatment of Tg2576 mice reduced Ab40 levels but the effect on memory function was not reported (Yan et al 2003). Chronic treatment with rosiglitazone (5 mg/kg/day) facilitated Aβ clearance and reduced Aβ burden in the hippocampus and entorhinal cortex of 13-month-old transgenic (human APP-overexpressing) mice and reduced the expression of proinflammatory markers (Escribano et al 2010). Interestingly, 4 weeks of rosiglitazone treatment in this experiment were not enough to restore the hippocampal function for an accurate performance in the Morris Water Maze test but all cognitive deficits were normalized following the 16 week-treatment.…”

The Evolving Biology of Microglia in Alzheimer's Disease

“…In the context of AD, the activation of PPARγ has been shown to promote clearance of Aβ by "licensing" microglia as competent phagocytes, in part by upregulating CD36 [54]. Consequently, activation of PPARγ leads to rapid reductions in the levels of Aβ in mouse models of AD [51,[55][56][57].…”