gw-3965 and Cognition-Disorders

Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid β (Aβ), which is accompanied by a robust inflammatory response in the brain. Both of these pathogenic processes are regulated by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor γ (PPARγ). Agonists of LXRs have been demonstrated previously to reduce Aβ levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPARγ reduce the microglial expression of proinflammatory genes and have also been shown to modulate apoE expression. Here we investigate whether a combination therapy with both LXR and PPARγ agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPARγ agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate Aβ decreases in the hippocampus. Combined treatment with both agonists provoked a further increase in the expression of apoE and a decrease in the soluble and deposited forms of Aβ. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPARγ agonist in the combined treatment paradigm was able to counteract the elevation in plasma triglycerides that is a side effect of LXR agonist treatment. These results suggest that combined LXR/PPARγ agonist treatment merits further investigation for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Behavior, Animal; Benzoates; Benzylamines; Biomarkers; Cognition Disorders; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation Mediators; Liver X Receptors; Male; Mice, Transgenic; Microglia; Orphan Nuclear Receptors; Particle Size; Pioglitazone; Plaque, Amyloid; PPAR gamma; Presenilin-1; Proteolysis; Thiazolidinediones; Transcription, Genetic; Triglycerides

Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; ATP Binding Cassette Transporter 1; Benzoates; Benzylamines; Biomarkers; Cell Proliferation; Cerebral Cortex; Cognition Disorders; Dentate Gyrus; DNA-Binding Proteins; Excitatory Postsynaptic Potentials; Female; Fluorescent Antibody Technique; Gliosis; Hippocampus; Liver X Receptors; Long-Term Potentiation; Male; Mice, Transgenic; Nerve Tissue Proteins; Nestin; Neural Stem Cells; Nuclear Proteins; Orphan Nuclear Receptors; Protein Biosynthesis; tau Proteins; Up-Regulation