Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease

Abstract

Background: The continuously increasing association of Alzheimer’s disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer’s disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.

Flavonols as a Potential Pharmacological Intervention for Alleviating Cognitive Decline in Diabetes: Evidence from Preclinical Studies

“…The novel object recognition test assesses aspects of declarative memory by exploiting rodents' natural curiosity for novelty. It measures an animal's ability to recognize and remember novel objects by using the discrimination ratio, a measure based on the time the animal spends exploring novel objects compared to previously encountered objects [178,179,208]. The Y-maze test is used to assess working and short-term spatial memory in rodents.…”

“…The Y-maze test is used to assess working and short-term spatial memory in rodents. Animals are trained to enter and remain in the non-shocking arm of the three-arm maze, and memory performance is assessed by measuring the latency to enter the safe arm and the number of correct entries during the testing trials [28,74,178,179]. The open-field test is often used to rule out motor impairments and the influence of anxiety [27,42,74].…”

“…In vitro experiments performed in hippocampal neurons also indicated that PPARγ transcriptionally upregulates BDNF expression [178]. PPAR-γ agonists improved behavioral deficits and synaptic plastic-ity in an animal model of AD as well [179]. PPAR-γ is also capable of modulating immune cell activation and inhibiting NF-κB, which ultimately downregulates the expression of pro-inflammatory genes and suppresses neuroinflammation [180].…”

Gastrodin ameliorates neuroinflammation in Alzheimer’s disease mice by inhibiting NF-κB signaling activation via PPARγ stimulation

“…PPARγ, a ligand-activated transcription factor, plays an important role in the pathological process of AD, which can serve as a neuroprotective target [ 3 ]. Meanwhile, many PPARγ agonists have been proven to produce neuroprotective effects in both the cellular and animal models of AD [ 4 , 5 ]. PPARγ is primarily activated by phosphorylation.…”

Recent Insights into the Role of PPARs in Disease

“…Steinke et al describe a novel PPARβ/δ and PPARγ dual agonist, which demonstrates striking beneficial effects in a mouse model (3xTgAD) of Alzheimer’s disease [ 13 ]. PPARγ agonists had been tested for this indication already before in several studies, but the effects were limited due to the poor penetration of the blood–brain barrier requiring high doses and observed severe side effects in clinical trials [ 14 , 15 , 16 ].…”