Manipulating Sleep/Wake Centers in AD-Like Mouse Models
Sleep problems, such as wakefulness at night and daytime napping, are common in patients with Alzheimer disease (AD). While sleep disturbances are often considered to be a consequence of neurodegeneration, we are taking another look. Data suggest that sleep disturbances occur very early in the course of the disease and might possibly contribute to AD-associated pathologies as well as the onset of cognitive symptoms including mild cognitive impairment (MCI). By switching sleep on and off, we will be able to assess whether sleep disturbances, such as unusual sleep duration and sleep fragmentation, are an early factor that contributes to the risk of developing AD.
Recent studies link disturbances of the sleep-wake cycle to the onset and amount of amyloid deposition. Given that patients with preclinical AD both report and display sleep abnormalities, it is of great interest to understand the underlying mechanism of these changes. The objective of our study is to elucidate the process that controls levels of amyloidogenic proteins, such as Aβ und tau, in the first place, and later leads to Aβ and tau aggregation. Understanding how Aβ influences both tau levels and pathology in the context of changes in the sleep-wake cycle is also of great interest in this study and will likely provide key insights into AD pathogenesis.
To achieve these goals, we will manipulate centers in the brain of AD-like mouse models that control sleep or wakefulness, then utilize multi-modal techniques to study the effect of altered sleep on Aβ and tau levels as well as AD-associated pathologies. Using new techniques, we will further be able to manipulate specific forms of sleep that are considered to be protective and have been shown to decrease in patients with MCI.
These studies are unique in that they contribute to the understanding of whether and to what extent the sleep-wake cycle and specifically its dysregulation in individual sleep/wake-centers are critical during the development of MCI and AD. Further, our laboratory is one of the few laboratories worldwide that is utilizing multi-modal techniques, such in vivo microdialysis, electroencephalogram, viral vectors and others, in awake, freely moving animals routinely.
In summary, we will assess if and to what extent sleep disturbances affect both Aβ and tau pathology, which are AD lesions that likely occur at different stages of the disease. This will allow us to identify new therapeutic targets for AD as well as provide clues to whether improving sleep might be effective even later in the course of the disease (ie, when Aβ pathology is already present and tau pathology starts to develop).
About the Researcher
I started to focus on research related to Alzheimer disease in 2010, when conducting my PhD thesis work in the laboratory of Prof. Mathias Jucker at the University of Tuebingen, Germany. During that time, my work focused on the characterization of the Aβ peptide in regard to its prion-like properties. In 2015, I graduated from the University of Tuebingen, Germany, with highest honor. Later in 2015, I joined the laboratory of Dr. David Holtzman, at Washington University in St. Louis, as a postdoctoral research fellow to examine the interplay of the sleep-wake cycle and Alzheimer disease.
In my third year as a PhD student, the institute I worked for opened its doors to the community for an open house event called “Fascination Brain.” My colleagues and I in the Cellular Neurology group gave short presentations about the history of Alzheimer disease (AD), potential diagnostics and therapeutic ideas. We also offered lab tours with hands-on activities. When finishing one of my tours, an elderly man, about 80 years old, stopped me and asked whether he could introduce me to his wife. She had been diagnosed with AD a couple of years ago. I am not a physician, but I could see that she could not pay as much attention as he maybe wanted her to. After listening to him for a couple of minutes, I understood how difficult their daily life must be, although he never complained. In fact, he asked me several times for advice on what else he could do. Should he schedule additional MRI scans? Could they re-assess her CSF testing? I could not give him any answers he hadn’t already gotten from her neurologist. Before they left he thanked me for all the work we are doing every day. He then looked at his wife and said: “Yes, there are difficult days, but today is a good one!” And then both of them smiled. I was moved to tears when I saw that he--at the age of 80--came to this event hoping to find anything that could help her. It has always been my passion to do research, and as a neuroscientist I have, to some degree, chosen not to have contact with patients that are suffering from AD or other neurodegenerative diseases. However, while pursuing a scientific career I think it is important to remind ourselves everyday that the ultimate goal is to find a way to help people that are or will be diagnosed with this devastating disease.
First published on: July 6, 2017
Last modified on: January 11, 2019