Targeting the Endosome for Alzheimer's Drug Discovery
Apolipoprotein E4 (ApoE4) status is the primary and biomedically most important risk factor for Alzheimer’s disease (AD). We have found a novel mechanism by which ApoE4 weakens synaptic strength in neurons, which led us to identify a promising novel endosomal drug target. This proposal aims to establish the necessary mechanistic and infrastructural baseline to screen for modifiers of endosomal function and for discovering novel potential methods to target the endosome in vitro and in vivo. This is necessary for the evolution of a conceptually novel and therapeutically effective preventive approach to AD, at least for the majority of patients carrying the ApoE4 allele.
Apolipoprotein E4 status is the primary and biomedically most important risk factor for Alzheimer’s disease. We have found that upon internalization by neurons, ApoE4 leads to an endosomal vesicular trafficking defect that sequesters ApoE receptors and neurotransmitter receptors in the endosome, thereby weakening synaptic strength. Based on available structural and functional data, we predicted and experimentally demonstrated that it is possible to modify ApoE structure as well as endosomal function to restore normal ApoE recycling, revealing this approach as a promising novel drug target.
Thus, this project investigates the endosome as a novel and largely unexplored target for drug development. We have presented ample experimental evidence for the validity of the target and the feasibility of developing drugs targeting this endosomal protein. Successful completion of the project would establish a novel therapeutic approach to AD that has the potential to abolish the ApoE4 risk for developing the most frequent late-onset form of the disease.
About the Researcher
Dr. Herz was born in Bad Mergentheim, a small town in southern Germany. He studied at the University of Heidelberg from 1977-1983, where he also completed work on his doctoral thesis in pharmacology with Prof. Gunter Schultz. After graduating from medical school in 1983, he practiced medicine as a surgical resident in Germany and England. In 1985, Dr. Herz joined the laboratory of Dr. Keith Stanley at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, where he discovered a novel member of the low-density lipoprotein (LDL) receptor gene family, the LDL receptor-related protein (LRP). In order to continue his studies on the role of LRP in cholesterol metabolism, in particular to investigate a hypothesized role of this gargantuan cell surface receptor in the transport of dietary lipids from the gut to the liver, in 1989, he joined the laboratory of Drs. Michael Brown and Joseph Goldstein, who shared a Nobel Prize in 1985 for their research involving a familial form of hypercholesterolemia.
In subsequent research, Dr. Herz proved that LRP functions in the transport of dietary lipids. He identified the first mechanisms by which lipoprotein receptors engage in cellular signaling in neurons and in smooth muscle of the vasculature, and showed that these signaling pathways are essential for the development of the brain, synaptic function and maintenance of vascular wall integrity. In 1991, Dr. Herz joined the faculty of the Department of Molecular Genetics at UTSWMC as an assistant professor. He was promoted to associate professor in 1995 and to the rank of professor in 1998. He has received fellowships from the Boehringer Ingelheim Foundation and the European Molecular Biology Laboratory. In 1991, he was selected as a Syntex Scholar and for a Lucille P. Markey Scholar Award. He became an established investigator of the American Heart Association in 1996.
In 2001, Dr. Herz was honored with the prestigious Wolfgang Paul Award of the Humboldt Society of Germany and the Ministry of Education of Germany for his work on the role of ApoE receptors in Alzheimer's disease. He became the Thomas O. and Cinda Hicks Family Distinguished Chair in Alzheimer's Disease Research in 2002, and received the Heinrich-Wieland Prize for Excellence in Lipid Research in 2007. In 2010, he was selected for a Humboldt Professorship on the basis of his contributions to the field of Alzheimer’s disease research.
Alzheimer's disease (AD) is one of the most pressing biomedical problems of our times, one that we must solve quickly to salvage our ability to provide comprehensive health care to our aging populations. It is also one of the most intriguing intellectual challenges. The mechanisms and risk factors that cause the aging brain to go into self-destruct mode are both vexing and fascinating. From the study of these disease mechanisms, we can also learn much about how the brain normally functions. Our work on the neurophysiology of lipoprotein receptors, which is the basis of this proposal, has provided the field with several conceptually novel insights into how the brain processes information and how this information is being translated into memories and fear responses. Along the path of exploring these mechanisms, we believe that we have found out how ApoE4, the most important risk factor for late-onset AD, causes this risk. This has opened the door for us to explore an exciting novel approach to testing, as well as to develop an innovative prevention approach.
On a personal level, I have been touched by AD through a relative with Down syndrome. Everyone afflicted with Down syndrome will effectively develop AD around the age of 50, because of the extra copy of the amyloid precursor protein on the duplicated chromosome 21. Therefore, Down syndrome is actually the most frequent, though also least noticed, form of early onset Alzheimer’s. Witnessing the decline of a relative due to this disease is a revelation no scientific article or book can appropriately describe or convey.
First published on: August 31, 2016
Last modified on: June 30, 2019