Developing a New Alzheimer’s Drug that Improves Lipid Metabolism in the Brain

Weiwei Fan, PhD
The Salk Institute for Biological Studies (La Jolla, CA)

Mentors

Ronald Evans, PhD
The Salk Institute for Biological Studies (La Jolla, CA)
Lawrence Goldstein, PhD
University of California, San Diego (La Jolla, CA)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to September 18, 2020
Disease:
Alzheimer's Disease
Award Amount:
$150,000
Grant Reference ID:
A2018325S
Award Type:
Postdoctoral Fellowship
Award Region:
US Southwestern
Weiwei Fan, PhD

Targeting Ppard in Alzheimer's Disease

Summary

Peroxisome proliferator-activated receptor delta (PPARδ) is a protein that is present in the brain. It is suggested to have important functions in brain. This proposal will help us understand its exact functions in brain. I will also test whether we can target PPARδ to treat Alzheimer’s disease (AD). 

Details

The goal of my research project is to understand the contribution of PPARδ (peroxisome proliferator-activated receptor δ), a master transcriptional regulator of lipid metabolism, in the pathological development of Alzheimer’s disease (AD), and to evaluate the therapeutic potential of PPARδ activation in a mouse model of AD. I will first determine the genome-wide binding sites (cistrome) of PPARδ in primary mouse cortex neurons, followed by the evaluation of changes in global gene expression (transcriptome) upon PPARδ activation. The results from both cistromic and transcriptomic analyses will identify direct target genes of neuronal PPARδ and elucidate its endogenous functions in neuron. I will further investigate the in vivo function of neuronal PPARδ and its role in AD by specifically deleting neuronal PPARδ in the 5xFAD transgenic AD mouse model. AD-related behavioral and pathological phenotypes will be assessed during disease progression in these mice, which will reveal the contribution of neuronal PPARδ dysfunction to lipid dysregulation and AD development. Lastly, I will evaluate the therapeutic potential of a novel PPARδ agonist that passes through the blood-brain barrier in human AD neurons and the 5xFAD transgenic AD mouse model. Transcriptomic analysis will also be performed in these models to understand PPARδ-induced transcriptional changes that drive the potential benefits against disease pathology.

Recent failures of multiple AD clinical trials that target the amyloid-β (Aβ) pathway highly suggest there are unknown key pathophysiological events of AD, beyond the Aβ pathway, that demand alternative therapeutic approaches. The brain is the most cholesterol-rich organ in the body, and next to adipose tissue, the most lipid-rich.  Lipid metabolism plays an essential role in maintaining normal brain functions and lipid dysregulation has been strongly associated with neurodegenerative diseases including AD. A better understanding of the regulation of lipid metabolism in the brain could help identify the next promising therapeutic targets. My research proposal focuses on PPARδ, a master regulator of lipid metabolism in the brain. Upon completion, my study will reveal the roles of PPARδ and its control over lipid metabolism in AD, and identify an alternative therapeutic approach that would potentially prevent or treat AD by improving lipid metabolism. 

About the Researcher

Dr. Fan is currently a staff scientist at the Salk Institute for Biological Studies. He was originally trained as a mitochondrial biologist in the laboratory of Dr. Douglas Wallace at the University of California, Irvine, where he created and characterized multiple mouse models that contain mitochondrial DNA (mtDNA) mutations. His work was among the first to establish the contribution of mtDNA mutations to pathological conditions in vivo and demonstrated the presence of a maternal germ-line selection mechanism that eliminates deleterious mtDNA mutations. Upon finishing his PhD training, Dr. Fan shifted his research focus from the mitochondrion into the nucleus and joined the group of Dr. Ronald Evans at the Salk Institute to study how the nucleus controls mitochondrial functions through transcriptional regulations by nuclear hormone receptors. His work at the Salk Institute has identified muscle PPARδ as a master regulator of lipid and glucose metabolism, which upon activation by exercise, induces a shift of the mitochondrial energy substrate utilization from glucose to fatty acid. Using both gain- and loss-of-function mouse models, he has demonstrated that such a PPARδ-dependent energy substrate shift is required to achieve maximal endurance enhancement by exercise training, and that the pharmacological activation of muscle PPARδ mimics exercise in activating the substrate shift and boosting endurance performance. He has also identified the orphan nuclear hormone receptors ERRα and ERRγ as the master transcriptional regulators of mitochondrial energy metabolism, which directly bind to the majority of mitochondrial energetic genes and positively regulate their expression.

Personal Story

I consider myself a mitochondrial biologist and have always been fascinated by those powerful energy plants in our bodies that provide over 90 percent of the energy. It was a great fortune for me to join the laboratory of Dr. Douglas Wallace, a renowned expert in the field of mitochondrial biology, for my PhD training. My PhD work focused on mitochondrial DNAs, the only extrachromosomal DNAs in mammalian cells that encode essential components of the mitochondrial energy apparatus, and the contribution of their mutations in pathological conditions including cancer, myopathy, neurodegenerative diseases, etc. Upon finishing my PhD study, I have determined to devote myself to studying mitochondrial functions for my research career. Knowing that mitochondria are tightly controlled by the nucleus, I decided to further explore the transcriptional regulation of mitochondrial functions for my postdoctoral training. Therefore I joined the laboratory of Dr. Ronald Evans, who is an authority on a special family of transcription factors, named nuclear hormone receptors, that control many physiological functions, including mitochondrial metabolism. During my postdoctoral study, I mainly focus on two types of transcriptional regulations of mitochondrial functions: the selection of mitochondrial energy substrate utilization between glucose and fatty acid through the nuclear hormone receptor PPARδ, and the direct control of overall mitochondrial energy metabolism and biogenesis through ERRα and ERRγ.

Mitochondrial energy metabolism, which includes lipid metabolism, is crucial for neuronal functions and represents a promising therapeutic target for neurodegenerative diseases, including Alzheimer’s disease (AD). This project funded by the BrightFocus Foundation provides a great opportunity to explore the function of PPARδ in the development of pathological alterations during AD and allows the evaluation of an alternative therapeutic approach for AD by targeting PPARδ and lipid metabolism. I sincerely appreciate this opportunity and hope my proposed research could lead to the development of a valid therapeutic strategy for AD.

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