Selective PPARγ agonism attenuates pathologies and improves cognitive deficits in Alzheimer's disease

Abstract

The continuous increase association of Alzheimer's disease (AD) with the increasing aged population and mortality rate indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Alzheimer's disease is primarily classified into early-onset (genetic) and late-onset (sporadic) depending on the age of the onset. Metabolic disease (e.g., obesity, insulin resistance) is associated with an increased risk of developing AD. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial regulator of glucose metabolism, and activation of PPARγ with thiazolidinediones (TZD) have been reported to improve cognition in mouse models of AD as well as in AD patients. However, full agonists such as pioglitazone display reduced blood-brain barrier (BBB) permeability, thus requiring high dosing and are associated with several adverse side effects. This work aimed to address this issue as an essential step in consideration of targeting PPARγ with novel compounds in delaying the progression or treatment of AD. In the current study, we present support for selective PPARγ agonist AU-9 to influence the pathologies of AD and compared with full agonist pioglitazone. First, through computational and cell culture work, we established AU-9 as a PPARγ agonist with selectivity in the ligand-binding domain of the PPARγ gene. Next, we found improvement in behavioral tasks and hippocampal synaptic plasticity in a triple transgenic mouse model of AD. We found evidence for the role of neurotrophins such as Brain-derived neurotrophic factor to influence the synaptic plasticity. Furthermore, we investigated the effects of AU-9 on amyloid pathology, neuroinflammation, and impaired energy regulation in the brain and found improvements in these pathologies. The results reported here support the view that selective PPARγ agonism by AU-9 may be helpful in the clinical management of AD; accordingly, the work discusses further steps towards translation of the present findings.