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Cells
Volume 12
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10.3390/cells12081116
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Article

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

by
Ian Steinke
1,
Manoj Govindarajulu
1,
Priyanka Das Pinky
1,
Jenna Bloemer
2,
Sieun Yoo
1,
Tracey Ward
3,
Taylor Schaedig
1,
Taylor Young
1,
Fajar Setyo Wibowo
1,
Vishnu Suppiramaniam
1,4 and
Rajesh H. Amin
1,*
1
Department of Drug Discovery and Development, Auburn University, Auburn, AL 36879, USA
2
Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY 10027, USA
3
Department of Pharmaceutical Sciences, Ferris State University, Big Rapids, MI 49307, USA
4
College of Science and Mathematics, Kennesaw State University, Kennesaw, GA 31044, USA
*
Author to whom correspondence should be addressed.
Cells 2023, 12(8), 1116; https://doi.org/10.3390/cells12081116
Submission received: 31 December 2022 / Revised: 23 March 2023 / Accepted: 4 April 2023 / Published: 8 April 2023
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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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.
Keywords: peroxisomal proliferator activating receptor; in silico drug design; neurodegeneration; Alzheimer’s disease; synaptic plasticity; behavioral deficits; dendritic spines peroxisomal proliferator activating receptor; in silico drug design; neurodegeneration; Alzheimer’s disease; synaptic plasticity; behavioral deficits; dendritic spines

Share and Cite

MDPI and ACS Style

Steinke, I.; Govindarajulu, M.; Pinky, P.D.; Bloemer, J.; Yoo, S.; Ward, T.; Schaedig, T.; Young, T.; Wibowo, F.S.; Suppiramaniam, V.; et al. Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease. Cells 2023, 12, 1116. https://doi.org/10.3390/cells12081116

AMA Style

Steinke I, Govindarajulu M, Pinky PD, Bloemer J, Yoo S, Ward T, Schaedig T, Young T, Wibowo FS, Suppiramaniam V, et al. Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease. Cells. 2023; 12(8):1116. https://doi.org/10.3390/cells12081116

Chicago/Turabian Style

Steinke, Ian, Manoj Govindarajulu, Priyanka Das Pinky, Jenna Bloemer, Sieun Yoo, Tracey Ward, Taylor Schaedig, Taylor Young, Fajar Setyo Wibowo, Vishnu Suppiramaniam, and et al. 2023. "Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease" Cells 12, no. 8: 1116. https://doi.org/10.3390/cells12081116

APA Style

Steinke, I., Govindarajulu, M., Pinky, P. D., Bloemer, J., Yoo, S., Ward, T., Schaedig, T., Young, T., Wibowo, F. S., Suppiramaniam, V., & Amin, R. H. (2023). Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease. Cells, 12(8), 1116. https://doi.org/10.3390/cells12081116

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