Mechanisms of Neuronal Dysfunction in Early Alzheimer’s Disease

Marc A. Busche, MD, PhD
University College London (London, England, UK)
Year Awarded:
Grant Duration:
July 1, 2019 to June 30, 2022
Alzheimer's Disease
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Marc A. Busche

In Vivo Cellular Imaging and Treatment of Hippocampal Dysfunction in Alzheimer Models


This proposal aims to identify the earliest neurobiological events underlying the development and progression of Alzheimer’s disease (AD). We will explore in particular the effects that tau and amyloid proteins seen in the brains of patients with AD have on the activity of interacting nerve cells in the hippocampus, a brain region which is known to be important for learning and memory. We will test an innovative therapeutic strategy and evaluate its ability to repair abnormal activities of nerve cells. These studies will not only increase our knowledge about the neurobiology of AD but also accelerate our therapeutic efforts to protect nerve cells and rescue learning and memory functions.


Using cutting-edge imaging techniques to monitor brain activity in real time will help us understand and ultimately treat AD.

Within the brain, the hippocampus is an area critically involved in learning and memory, and its dysfunction is a key feature of AD and related neurodegenerative disorders. However, the cellular basis of hippocampal dysfunction in AD is not currently known. 

In this project, we will use high-resolution, laser-based microscopy in novel mouse models of AD to directly image the hippocampus, cell by cell, as it starts to develop disease. We will determine how the impairment of individual nerve cells and their connections contributes to abnormal brain activities including epileptic activity that frequently occurs in individuals with AD. Finally, we will test the effects of a new therapeutic strategy that if successful could be immediately used in clinical trials. 

Our research project is unique and innovative because for the first time we will employ an imaging technique that enables us to generate real-time functional views of nerve cells including their processes in the AD brain. Collectively, the experiments are designed to make a significant impact on our understanding, the treatment and prevention of hippocampal cellular and network dysregulation in AD.

About the Researcher

I am currently a Programme Lead at the UK Dementia Research Institute at University College London. I performed my graduate studies in Germany in the laboratory of Arthur Konnerth, where I identified the pivotal role of early neural hyperactivity in the amyloid-plaque bearing Alzheimer brain. Then, I stayed at the Technical University of Munich to complete a residency in psychiatry and psychotherapy. While a resident, I conducted research as a tandem group leader at the Munich Cluster for Systems Neurology, focusing on the role of sleep-related long-range brain circuit dysfunction in Alzheimer’s disease (AD). As a recipient of the EMBO Long-Term Fellowship, I performed research with Bradley Hyman at MassGeneral Institute for Neurodegenerative Disease and Harvard Medical School, in which we identified that tau and amyloid work together to impair brain function in AD, and that tau predominates for certain aspects of that impairment. I am a board certified psychiatrist.

Personal Story

I was devastated when I learned, just 7 or 8 years old, that my father had developed a rare neurologic condition. It was a many years long journey with innumerable visits to hospitals until one doctor finally figured out the name of this illness and what it meant to him and his family – yet he couldn’t offer a cure. Being able to treat or even cure brain diseases like the one my father had developed has been a dream of mine since then and I decided to study medicine. In Germany, where I grew up, medical students typically take off some time to perform a full-time research project. I wanted to learn how to do neuroscience research and joined Arthur Konnerth’s lab in Munich. Arthur’s lab had just pioneered a novel brain imaging technique, called multiphoton calcium imaging, that allowed for the first time to study the function of nerve cells in the intact brain in vivo. Until then, researchers had to rely on reduced brain preparations such as slices or cell cultures, so this new technique was a true paradigm shift for neuroscience research. I wanted to work on a scientific problem that was significant and related to my interest in medicine and brain disease and I was therefore very grateful that I had the privilege to use this new imaging technique in a mouse model of Alzheimer’s disease. We wanted to ask the question what happens to nerve cells in the vicinity of amyloid-beta plaques, which are a hallmark lesion in the AD brain. In retrospect I consider this time as being one of the happiest I can ever recall. I then completed medical school and also a PhD, in which I followed up on important questions that arose during my research time as a medical student. Because I enjoyed working in the clinic as well, I started a residency in psychiatry (­in Germany patients with AD and other neurodegenerative diseases are seen by psychiatrists). Today, I appreciate that this was the first time that I had truly functioned as a clinician scientist doing clinical training during the day and research in the evenings and often weekends, and I loved it. Caring for patients with AD and other neurodegenerative diseases allows me to see the whole disease picture and gives me the capacity to perceive which clinical questions we need to address scientifically to achieve the target of a cure. As a clinician I see individual patients and their families and help them navigate their illness, but as a scientist I am able to work towards a better understanding of disease that (hopefully) leads to novel treatments that could benefit millions of people around the world. I could not be more grateful to the generous donors of the BrightFocus Foundation who make this research possible and allow me to continue working towards cures for neurodegenerative diseases. 

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