Age-dependent Neuronal De-Differentiation in Alzheimer's Patient-Derived Induced Neurons
Everybody ages, and unfortunately, this banal fact represents a huge health threat for us, because old age is the major risk factor for many human diseases with Alzheimer’s Disease leading the way. Our laboratory has recently found a way to reprogram cultured skin cells from Alzheimer patients directly into brain neurons, which are unique for each patient and also biologically ‘remember’ how old the patient was. By looking at all genes used by these cells, we could already make some exciting new discoveries, as it looks like the neurons from Alzheimer patients seem to have partially lost their memory regarding their own identity and function in the body; in some ways similar to cancer cells. In this project we aim to better understand this connection and try to find ways to give Alzheimer neurons their own memory back.
To investigate age-dependent mechanisms of sporadic Alzheimer's Disease (AD), my laboratory reprograms skin cells from AD patients and aged cognitively normal donors into induced neurons (iNs), and investigate these cells as a ‘brain model’ that is not only genetically unique to each patient, but that also biologically ‘remembers’ the age of the individual.
By measuring levels of all genes used by these iNs, we could already make the exciting discovery that the neurons from AD patients appear to have partially lost their memory regarding their own identity and function in the body; which in several ways shares molecular signatures of cancer. In this project we first aim to deeply characterize and understand this phenomenon of neuronal de-differentiation using a powerful next-generation sequencing and computation-assisted characterization of the epigenetic landscape of the iNs, as well as the iNs’ functional properties and survival strategies. Next, it is known from cancer that impaired cellular metabolism, the chemical processes that transacts energy and cellular building blocks, might drive cellular de-differentiation. In a second aim we will assess the metabolic pathways in AD and control iNs to hopefully unravel regulatory nodes that might serve as alterable switches for potential treatment strategies. We anticipate that our work will significantly benefit from the cancer research field, where scientists have worked for decades to develop drugs to prevent de-differentiation by targeting
The iN model system is the only human patient-specific neuronal model system known so far that allows for the integration of age-related mechanisms. We are determined to fully exploit this opportunity by generating iNs from a large number of clinically well-characterized patients, and analyzing these cells using several state of the art omics technologies. Ultimately, we work to try to find ways to give AD neurons their cellular memory back.
This project aims at bringing a substantially new perspective onto the pathogenesis of AD and might give rise to yet unexpected treatment strategies borrowed from the cancer field. The results from this research might holds exciting potential for personalized medicine approaches in the AD field, as well as for other
About the Researcher
Throughout my scientific career, my focus was on studying neurological disorders and brain aging by using human stem cell and reprogramming technologies, paired with cellular and molecular neuroscience. My research as a graduate student under the supervision of Oliver Brüstle at the University of Bonn in Germany provided me with a solid foundation in neurodegeneration, human pluripotent stem cell biology, and reprogramming techniques. Back then, we devised some of the earliest studies on the use of human pluripotent stem cells, both transgenic embryonic stem cells and iPSCs, to model and study AD. One of our major findings was that human stem cell-derived neurons possess a specific responsiveness towards potential drugs, and that these cells are more predictive than commonly used cancer cell. As a postdoctoral researcher at the Salk Institute under the supervision of Rusty Gage, I was fortunate to have the environment and support to strengthen my experimental skills in neuroscience, next-generation sequencing and bioinformatics analysis of big biological data sets. Combining my expertise in iPSCs biology with functional cellular neuroscience we could show how lithium affects the intrinsic hyperexcitability of Bipolar Disorder patient-derived neurons. Further, based on my long lasting interest in the study of age-related neurodegeneration, I initiated a project that showed that direct conversion of fibroblasts in induced neurons (iNs) preserves signatures of cellular aging, while iPSC reprogramming erases them. Follow-up work on iNs from my new lab in Innsbruck in collaboration with the Gage lab, as well as from several other labs around the globe has now further extended our knowledge and revealed how the nuclear pore, mitochondria, protein homeostasis, and epigenetic aging signatures are reflected in iNs, together rendering the iN system as a unique, patient-specific, and ‘age-equivalent’ neuronal model for human diseases. My overall research goal is to harness my expertise in cell biology, neuroscience, and systems biology to fully exploit the iN system to unravel the molecular key players that define progressive human cellular age and set the stage for age-related neurodegenerative diseases. My work aims to contribute to finding new personalized diagnostics and treatments that may target pathogenic mechanisms of age-related neurodegenerative disease, specifically sporadic AD.
Even before my decision to becoming a scientist, my curiosity has been always drawn to the incomprehensible process of aging, and how it relates to AD and the many other diseases that tend come with advanced age. I was certain that we only need to stop aging to cure all of them at once – and I still am! Humans can become 80, 90, even 100 years old, and I always wanted to study the human system, not short-lived animals, to understand human aging. During my early studies in biomedicine, I became more and more aware of human diversity and how each individual is different, and that it will be necessary to study complex diseases using human models that are as close to the patient as possible. During an undergrad research internship in the Brüstle lab, my supervisor Philipp Koch showed me how he could differentiate stem cells from actual people into functional neurons - I became fascinated by beauty and the power of this concept and never turned away since. Today, we are able to generate human patient-specific models that not only reflect the genetics of a given individual, but also capture the age of the individual. This technology opens incredible possibilities towards better understanding brain aging and AD, and also for testing new treatment strategies – potentially in a patient-specific manner in the foreseeable future. Importantly however, none of these visions have substance without the patients and control participants that donate skin cells for research, and the funding agencies that support new groundbreaking and risky research. I am deeply thankful for the support by the BrightFocus foundation and its donors that support this project. At this early stage in my career, this BrightFocus grant is vital for me to turn ideas into actual knowledge, and also gives me the confidence that we can actually make a meaningful difference for patients.
Schlachetzki JC, Toda T, Mertens J. When function follows form: Nuclear compartment structure and the epigenetic landscape of the aging neuron. Experimental Gerontology. 2020 Feb 14:110876. PMID: 32068088
Traxler L, Edenhofer F, Mertens J. Next-generation disease modeling with direct conversion: A new path to old neurons. FEBS Lett. 2019 Nov 12. doi: 10.1002/1873-3468.13678. [Epub ahead of print] Review. PubMed PMID: 31715002
First published on: July 2, 2019
Last modified on: March 20, 2020