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. Many reports verify direct pathological links of AD with diabetes, which highlights the contribution of diabetes to the development of AD. Thiazolidinediones (TZDs) are insulin sensitizing peroxisomal proliferator activating receptor-gamma (PPARγ) agonists. TZDs are promising agents for improving cognition in patients with AD because they reduce amyloid and tau pathologies, display anti-inflammatory properties and improve memory impairments in diabetic mice. However, they display poor blood-brain barrier (BBB) permeability, thus requiring high dosing, and are associated with several adverse side effects. We have developed a novel PPARγ (AU-9) in-silico that has selective amino acid interactions in the PPAR γ  ligand-binding domain. This design avoids the unwanted side effects of current PPAR γ agonist, including edema and effects on the heart. Furthermore, AU-9 displays enhanced BBB permeability, thus requiring lower concentrations to promote protection against AD.

We hypothesize that our lead compound (AU-9), a selective dual Peroxisome proliferator-activated receptor δ/γ modulator improves cognitive deficits and neurodegeneration associated with AD.

Methods:  We treated nine-month-aged triple-transgenic AD mouse (3xTg-AD) and C57BL/6J control mice with a novel and selective dual Peroxisome proliferator-activated receptor δ/γ modulator AU-9 for one month. Behavioral studies and electrophysiological experiments were performed to determine improvement in cognitive and synaptic plasticity deficits. Golgi cox staining to evaluate the hippocampal and cortical dendritic spine morphology and density; Nanostring neurodegeneration gene expression analysis to determine changes in various genes involved in hippocampal neurotransmission, plasticity and neurodegeneration; and Neurotrophin activity assay to measure various neurotrophins were performed. In vitro studies involving AU-9 mediated PPARg - BNDF promoter activity and downstream effector signaling were investigated to determine the PPAR γ/δ activity of AU-9 on possible mechanisms for promoting neurogenesis.

Results: Behavioral studies and electrophysiological studies (measuring hippocampal long-term potentiation) showed improvement of synaptic and memory deficits in the transgenic mice with treatment. Improvements in dendritic spine density were noted with AU-9 treatment on Golgi cox staining. Gene expression analysis indicated improved neurotrophin expression including BDNF. Biochemical assays showed increased expression of glutamate receptors, glutamate regulatory proteins, expression of PSD-95 and Arc proteins essential for synaptic maturity and plasticity. 

Conclusion: Our results indicate that AU-9 offers potential therapeutic benefits for mitigating neurodegeneration and memory deficits associated with AD. One possible mechanism may involve enhancing neurotrophin expression (BDNF) and thereby attenuating neurodegeneration.  Pharmacokinetic studies will allow us to determine the minimal amount of AU-9, needed for brain bioavailability for its potential therapeutic benefits. These findings will allow us to enhance AU-9 towards a potential therapeutic agent for fighting Alzheimer’s disease.