Understanding the Role of Apolipoprotein E in Microglia

Edoardo Marcora, PhD
Icahn School of Medicine at Mount Sinai (New York, NY)

Co-Principal Investigators

Anne Schaefer, MD, PhD
Icahn School of Medicine at Mount Sinai


Alison M. Goate, D.Phil
Icahn School of Medicine at Mount Sinai
Year Awarded:
Grant Duration:
July 1, 2017 to June 30, 2021
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern
Edoardo Marcora, PhD

As long as I can remember, I have been fascinated by nature and the methods of science. If the choice on TV was a cartoon or documentary about the human body, I would pick the latter.

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Understanding the Role of Apolipoprotein E in Microglia


Human genetic studies strongly point to apolipoprotein E (APOE) and microglia (the immune cells of the brain) as,  respectively, the most important gene and cell type in the chain of events leading to Alzheimer’s disease(AD), a common disorder in the elderly in which the brain is damaged and memories falter. In normal conditions, microglial cells do not make APOE; however, in disease conditions, they sense the brain damage and respond by churning out APOE. It is unclear why this occurs. The goal of this project is to answer this question in a mouse model where the APOE gene is switched off in microglia.


The goal of this project is to elucidate the functional role of apolipoprotein E (APOE) in microglia, the resident immune cells of the brain. The importance of APOE (a gene involved in cholesterol metabolism) has long been recognized in AD. Its impact on AD risk is akin to that of BRCA1 on breast cancer. However, our understanding of how APOE is able to so potently alter susceptibility to AD remains incomplete, thus impairing our ability to develop appropriate therapeutic strategies targeting APOE.

Recently, thanks to major advances in human genetics, it has become increasingly clear that not only APOE and cholesterol metabolism, but also the proper functioning of microglial cells, strongly modulates the risk of developing AD in old age. However, given that APOE plays key functions in peripheral immune cells that are very similar to microglia (eg, macrophages), it is surprising that the role of APOE in microglia is practically unexplored and remains largely unknown.

With the help of this grant, we are generating mice engineered to switch off the APOE gene only in microglia and performing molecular profiling without having to isolate microglial cells first. Instead, we are using microglia-specific translating ribosome affinity purification (TRAP) technology developed here at Mt. Sinai Icahn School of Medicine by Dr. Anne Schaefer. In mouse models, we will  compare and contrast the molecular makeup, structure, function, and behavior of normal microglial cells with those lacking the APOE gene, and this comparison will not be done after isolation and culture in a Petri dish, as it has been done in the past, but in the natural environment, the brain. Indeed, recent data demonstrate that when microglial cells are removed from the brain and cultured in vitro, they rapidly transform into something else. Moreover, recent data also show that in response to brain damage caused by aging, amyloid deposition, demyelination, and other insults, microglial cells activate several genes, including APOE, in order to more efficiently scavenge and clear tissue debris that are very rich in cholesterol due to the natural composition of the brain, which is mostly made of fats. The final aim of this grant is to examine how the response of microglia to brain damage (i.e., demyelination induced by treatment with cuprizone) is altered when the APOE gene is deleted. Analysis of these data will allow us to gain a better understanding of the role of APOE in microglia and therefore get a step closer to being able to OKeffectively target APOE and microglia for the treatment or prevention of AD.

About the Researcher

Dr. Edoardo "Dado" Marcora graduated summa cum laude from the University of Pavia, Italy with a degree in biological sciences. He then continued his training as a graduate student at the University of Colorado at Boulder, and as a postdoc at the California Institute of Technology in Pasadena, where he investigated the function of the Huntingtin gene in Huntington's disease, a neurodegenerative disorder. He then moved to Cambridge, UK, to train and work as a computational biologist in the Vertebrate Genomics group at the European Bioinformatics Institute (EMBL-EBI). Following that he moved back to the United States to join the Neuroscience Discovery department at Amgen in San Francisco, where he applied his wet lab (molecular and cellular neurobiology) and dry lab (human genetics and integrative genomics) expertise to drug hunting for AD. He recently moved back to academia as an associate professor in the departments of Neuroscience and Human Genetics & Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York, where he continues his basic research and translational efforts in AD using a state-of-the-art experimental and computational toolkit, in collaboration with Drs. Alison Goate and Anne Schaefer within the Ronald M. Loeb Center for Alzheimer’s Disease.

Personal Story

As long as I can remember, I have been fascinated by nature and had a desire to learn about it following the methods of science. If the choice on TV was between watching a funny cartoon or a BBC documentary about animals or the human body, I would always pick the latter. So much so that it became routine for me and my brother (see below) to watch at least one documentary a day and read books about several topics in natural sciences. I have never stopped learning about biology since then, and hopefully will until the very end, that is, if I am lucky enough not to be affected in old age by devastating disorders like Alzheimer's and Huntington's disease. I have come to know both of these conditions very closely as part of my research efforts and also at a personal level.

Another constant in my life is that I have been continually reminded (24/7 and starting even before being born) of the power of human genetics. I happen to have an identical twin brother, Samuele (aka "Lele"). There is no more obvious demonstration of the dramatic influence of genes on the human body and behavior than to be looking at another person as if you were looking at yourself in the mirror. He shares practically 100 percent of the information stored in my own DNA.

My interests is neurobiology sharpened when I started wet lab research at the University of Pavia as an undergraduate. I made it a personal mission to understand how genes influence the development and normal functioning of the brain, as well as their role in disease pathogenesis. Answering these kinds of questions has always been the beacon of my research, as I have not focused on any particular methodological approach (which is often the case in the hyper-specialized modern scientific enterprise), but rather forced myself to become proficient in a variety of tools and techniques spanning from wet and dry lab methods to software and drug development, as needed, to answer the question at hand.

My latest transition back to academia is aimed at integrating the diversified knowledge and skillset that I accumulated through all of these past experiences with the goal of bridging the gap (often referred to as "the valley of death") that separates basic research efforts in academia with those of big pharma. In my opinion, this gap has greatly hindered the progress toward developing efficacious therapies for AD. My goal is to contribute to the resolution of this important problem by bringing to bear recent advances in human genetics and integrative genomics and translating them in a mechanistic, systems-level understanding of disease that is rooted in human biology but also actionable from a drug development perspective. To achieve this, I am developing novel cellular and animal models (like the one proposed here) that better reflect the new biological insights stemming from human genetics. 

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