My Career – Chapter 4: Alzheimer’s Disease
Advancing Alzheimer’s Research through a Human-Mouse Chimeric Model
Context and Significance
During the final stages of my PhD at ULB (Université Libre de Bruxelles), I collaborated with Professor Pierre Vanderhaeghen’s team on a critical project. Starting in early 2015, I successfully balanced this work alongside completing my PhD before extending my time in Belgium for six months to focus exclusively on the research before leaving for Chicago. The project tackled one of the most pressing challenges in Alzheimer’s disease (AD) research: creating models that accurately capture human-specific neuronal pathology.
"Alzheimer’s disease is a brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. Alzheimer’s disease is the most common cause of dementia among older adults. In 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman [...] and found many abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary, or tau, tangles). These plaques and tangles in the brain are still considered some of the main features of Alzheimer’s disease. Another feature is the loss of connections between nerve cells (neurons) in the brain."
Our team developed and validated a human-mouse chimeric model that allowed human neurons to be studied in a natural environment, revealing human-specific vulnerabilities to AD pathology. Published in Neuron, this work was recognized globally for its scientific and societal impact. It even achieved Editor’s Choice in Science Translational Medicine, further underscoring its importance.
The project was not only a highlight of my career but also a masterclass in high-level collaboration. Combining my expertise in electrophysiology and imaging with the technological advancements pioneered by Pierre Vanderhaeghen’s lab, we advanced the understanding of Alzheimer’s in a way that had never been done before.
The Research: A New Lens on Alzheimer’s Disease
Our work centered on transplanting human neurons derived from pluripotent stem cells into the brains of mice with amyloid plaques, a hallmark of Alzheimer’s pathology. Unlike traditional cell cultures, this model captures the complexity of the disease within a living brain, offering unparalleled insights. Curious? See how human neurons fire in culture here or explore a glimpse of neuronal activity in a mouse brain here.
Key findings include:
Human Neurons’ Unique Vulnerability
“This fascinating paper shows, for the first time convincingly in vivo, that human neurons behave differently in response to fibrillary Aß than mouse neurons.” – Jochen Herms, Ludwig-Maximilians-Universität MunichNeurodegeneration Without Tangles
Remarkably, human neurons in this model underwent neurodegeneration without forming tangles, separating tau phosphorylation and conformational changes from neuron death.Broad Genomic Insights
Genome-wide expression analysis revealed the upregulation of genes related to myelination and the downregulation of genes linked to memory, cognition, synaptic transmission, and neuron projection, providing a deeper understanding of disease mechanisms.
My Contributions
In this interdisciplinary and fast-paced collaboration, I contributed in several impactful ways:
Electrophysiology
I performed detailed electrophysiological recordings to assess how transplanted human neurons matured and integrated into the mouse brain. This allowed us to track changes in active and passive electrical properties, providing critical insights into their synaptic function.Confocal Imaging
Using advanced imaging, I analyzed neuronal structure and marker expression, confirming the differentiation and integration of human neurons.Teamwork and Training
I trained a PhD student in electrophysiology and imaging techniques, ensuring the project’s continuity. Effective communication between teams and collaborators, such as Professor Bart De Strooper, was crucial to the project’s success.
Media Coverage and Public Recognition
The significance of this groundbreaking work extended well beyond the scientific community, drawing significant attention from both academic and general audiences. These articles and acknowledgments highlighted the innovative approach and its transformative potential for Alzheimer’s research:
- La Libre (French)
Featured in the influential French-Belgian media outlet known for its wide-reaching audience:
“This new model has allowed for better characterization of disease-related processes taking place in the brains of human patients.”
Read the article here | Translation here
- DRUG Target Review – News
The official statement underscored the accelerated pace of discovery enabled by this model:
“Now that we are able to investigate the disease by observing human cells directly, we can make progress in this field of research at a considerably faster pace.”
Read the article here
- Science Daily – News
Highlighting the ultimate goal of the research:
“The eventual end goal of the screening is to identify new drug targets within human cells themselves, something that was never possible before.”
Read the article here
- Feature in KUL News
Highlighted by KU Leuven for its role in advancing Alzheimer’s research:
“With this novel experimental technique, we can study how different cell types in the human brain respond to the Alzheimer’s pathology and hopefully unravel the link between amyloid and tau protein pathology – which leads to neuron death and is the holy grail of current Alzheimer’s research.”
Read the article here
- Feature in Electronics Specifier
Electronics Specifier celebrated the work for its innovative approach to neuroscience:
“This new chimeric model allows for a better characterization of the disease processes that actually take place in the brain of human patients.”
Read the article here
- Editor’s Choice by Science Translational Medicine
Our work was recognized as Editor’s Choice by Science Translational Medicine, emphasizing its interdisciplinary impact:“This recognition…highlights the wide-reaching implications of our Alzheimer’s research and its promise in addressing complex neurological diseases.”Read the article here
- Feature in Nature Reviews Neurology
Recognized in Nature Reviews Neurology for addressing a major limitation in Alzheimer’s models:“The human neurons transplanted into AD mice undergo major neurite dystrophy, neurodegeneration, tau pathological conformational changes, and severe cell death. These important AD hallmarks have not been shown to this extent in previous AD mouse models.”Read the article here
The Team: A High-Level Collaboration
Working with Pierre Vanderhaeghen, a globally respected neuroscientist, and Bart De Strooper, an Alzheimer’s expert of equal renown, was a career-defining experience. Their leadership and the collective expertise of the teams at ULB and VIB-KU Leuven created an environment of scientific rigor and innovation.
This collaboration extended beyond academia, connecting with industry leaders through the Stellar Project—a groundbreaking initiative uniting Janssen, Johnson & Johnson Innovation, VIB, KU Leuven, and UZ Leuven. With up to €5 million in funding over five years, Stellar aimed to overcome inefficiencies in translating basic molecular insights into diagnostics and therapeutics for neurodegenerative diseases like Alzheimer’s. This ambitious project fostered multidisciplinary research involving molecular neuroscientists, cognitive animal model experts, clinical neurologists, human imaging specialists, and Janssen R&D scientists.
My role included presenting research at scientific meetings and engaging in discussions with Janssen Pharmaceuticals as part of Stellar’s efforts. These interactions were critical in aligning academic advancements with translational goals, creating opportunities for impactful collaborations and paving the way for neuroprotective therapeutic strategies.
Impact and Reflections
The chimeric model we developed was not just a technical achievement but a conceptual leap forward, enabling researchers to study Alzheimer’s in a way that aligns more closely with human pathology.
What made this work special to me:
- The chance to apply my skills in electrophysiology and imaging to a high-stakes, innovative project.
- Collaborating with such a skilled and efficient team of researchers.
- The broad societal and scientific recognition of the work, which highlighted its importance.
This project remains a highlight of my career and a testament to the power of collaboration and interdisciplinary expertise.
Description
Alzheimer’s Disease Research
Advanced understanding of human-specific neuronal pathology through a collaborative human-mouse chimeric model, addressing critical challenges in Alzheimer's research.