Alzheimer's - Dementia, Author Interviews / 02.05.2024
Novel Neuron Model Recapitulates Human 4R Tauopathy: Sheds Light on Potential Therapeutic Target
MedicalResearch.com Interview with:
[caption id="attachment_61640" align="alignleft" width="110"]
Dr. Li Gan[/caption]
Dr. Li Gan PhD
Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases
Brain and Mind Research Institute
Weill Cornell Medical College
[caption id="attachment_61627" align="alignleft" width="150"] Dr. Shiaoching Gong[/caption]
Shiaoching Gong PhD
Helen and Robert Appel Alzheimer’s Disease Institute
Feil Family Brain and Mind Research Institute
Weill Cornell Medicine, New York, NY
MedicalResearch.com: What is the background for this study? Would you describe the process of making these neurons?
Response: Primary tauopathies are a group of progressive neurodegenerative diseases characterized by the pathological aggregation of 3R or 4R tau protein in neurons and/or glial cells, where 4R tauopathies are more common primary tauopathies. The exact pathological mechanisms remain elusive. There are currently no therapies available that can halt or reverse the spread of tau aggregates since the drug effects found in animal models are not always reproduced in human clinical trials. The development of tau therapies from human cells have become urgently needed. Induced human pluripotent stem cells (iPSCs) offer a unique model to better understand pathological mechanisms underlying human diseases and to develop human cell-based therapy. However, a major challenge to study 4R tauopathy is iPSC-derived neurons express very low levels of 4R Tau isoforms making it difficult to study 4R tauopathy and the mutations located in 4R Tau.
To address this need, we designed and engineered a robust human iPSC 4R tauopathy model using CRISPR/Cas9 technology. We first introduced specific mutations at the intron-exon 10 junctions and silent mutations within exon 10 to promote exon 10 inclusion, leading the increase of 4R isoforms expression in iPSC-derived neurons. Frontotemporal Dementia (FTD) mutation, P301S located in exon 10 is highly aggregation prone. To generate this human disease 4R tauopathy model, we then introduced this mutation to 4R iPSC to make it a 4RP301S iPSC line.
Dr. Li Gan[/caption]
Dr. Li Gan PhD
Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases
Brain and Mind Research Institute
Weill Cornell Medical College
[caption id="attachment_61627" align="alignleft" width="150"] Dr. Shiaoching Gong[/caption]
Shiaoching Gong PhD
Helen and Robert Appel Alzheimer’s Disease Institute
Feil Family Brain and Mind Research Institute
Weill Cornell Medicine, New York, NY
MedicalResearch.com: What is the background for this study? Would you describe the process of making these neurons?
Response: Primary tauopathies are a group of progressive neurodegenerative diseases characterized by the pathological aggregation of 3R or 4R tau protein in neurons and/or glial cells, where 4R tauopathies are more common primary tauopathies. The exact pathological mechanisms remain elusive. There are currently no therapies available that can halt or reverse the spread of tau aggregates since the drug effects found in animal models are not always reproduced in human clinical trials. The development of tau therapies from human cells have become urgently needed. Induced human pluripotent stem cells (iPSCs) offer a unique model to better understand pathological mechanisms underlying human diseases and to develop human cell-based therapy. However, a major challenge to study 4R tauopathy is iPSC-derived neurons express very low levels of 4R Tau isoforms making it difficult to study 4R tauopathy and the mutations located in 4R Tau.
To address this need, we designed and engineered a robust human iPSC 4R tauopathy model using CRISPR/Cas9 technology. We first introduced specific mutations at the intron-exon 10 junctions and silent mutations within exon 10 to promote exon 10 inclusion, leading the increase of 4R isoforms expression in iPSC-derived neurons. Frontotemporal Dementia (FTD) mutation, P301S located in exon 10 is highly aggregation prone. To generate this human disease 4R tauopathy model, we then introduced this mutation to 4R iPSC to make it a 4RP301S iPSC line.
Dr. Stern[/caption]
Robert A. Stern, Ph.D.
Professor of Neurology, Neurosurgery, and Anatomy & Neurobiology
Director of Clinical Research, BU CTE Center
Senior Investigator, BU Alzheimer’s Disease Research Center
Boston University School of Medicine
MedicalResearch.com: What is the background for this study?
Response: The link between playing American football at the professional level and later-life brain disorders like chronic traumatic encephalopathy – or CTE -- and ALS has received increasing attention over the past 15 years. Previous research has shown that former NFL players are more likely to die from CTE and amyotrophic lateral sclerosis (ALS) and more likely to report cognitive impairment, behavioral changes, and dementia during life. Despite previous research focusing on the later-life effects of playing American football at the professional level, the long-term effects of college football participation remain largely unknown.
We had two goals for this new investigation. The first was to conduct a survey of the current overall health status, including cognitive and other neurological disorders, of older former college American football players compared with men in the general population. The second goal was to examine the mortality rate and causes of death in a cohort of older former college football players. The target population for this study was all 447 former Notre Dame football players who were listed as seniors on the varsity rosters during the 1964-1980 seasons. This was the era of legendary coaches Ara Parseghian and Dan Devine. I should add that this study was fully independent of the University of Notre Dame.
