BIN1 as a Risk Factor in Tau Pathology in an Inducible Transgenic Model
Genetic studies have recently uncovered several genes that can elevate the risk of developing Alzheimer’s disease (AD), including the BIN1 gene as the second strongest genetic risk factor for late onset AD. My lab has generated a BIN1 transgenic model to mimic the increase of BIN1 protein in the brains of people with AD. My goal is to use this transgenic mouse model to investigate how BIN1 functions as a risk factor in AD. I expect that my proposed research will significantly advance the knowledge about BIN1's function in the physiology of the brain, and reveal how it contributes to AD pathology.
My lab has generated mouse models to explore the function of BIN1 in the brain. Using these models, I will investigate how BIN1 functions as a risk factor in Alzheimer’s pathogenesis.
Recent research has uncovered several genes that can elevate the risk of developing AD. Exactly how the genetic risk factors contribute to the disease is not readily apparent in most cases, and requires cellular and molecular biology investigations that use cultured cells and mouse models. The gene BIN1 is identified as the second most common genetic risk factor for late-onset AD. Very little is known on BIN1's function in the brain and how it is related to AD. I have begun to investigate BIN1 expression and the isoform diversity in the brains of patients with AD. BIN1 is present in multiple forms in the brain, all of which may have a different function. My lab has generated mouse models to mimic the increase or the decrease of BIN1 protein isoforms in the brain. My goal is to use these mice as in vivo models to investigate AD-associated pathology and behavior deficits so that we can learn how BIN1 functions as a risk factor in AD. I will also explore BIN1 function at the cellular level using in vitro techniques coupled with high resolution imaging.
The project described in this proposal will help us to extend the findings from other genetics research, including GWAS (genome-wide association studies) and in vitro studies, into an in vivo investigation using mouse models in order to establish BIN1 as a potential new candidate in AD pathophysiology. Investigating BIN1 function in the brain and assessing the involvement of BIN1 in the disease pathology using appropriate in vivo models is a vital and key step. Observing BIN1’s physiological function will help us to how its dysregulation might lead to AD.
If my hypotheses are correct, this project will highlight BIN1 as a new candidate for drug development. If BIN1 is found to be involved in disease pathogenesis, it will advance efforts towards targeting BIN1 as a potential strategy for disease modification. The study of BIN1 in the brain is a new area of research and determining the mechanistic link between this risk factor and AD etiology disease is important.
About the Researcher
Pierre De Rossi is a postdoctoral research scholar in the Department of Neurobiology at the University of Chicago. During his PhD work at the Lyon Neuroscience Center (France), he worked on the regulation of postnatal synaptogenesis and synaptic remodeling associated with learning and memory. His study highlighted a role for vascular endothelial growth factor (VEGF) in N-methyl-D-aspartate (NMDA) receptor trafficking via the activation of long-term potentiation signaling pathways at the post-synaptic sites (De Rossi et al, 2016). He also started to study the pathological aspects of the synapse called the limbic encephalitis (Mikasova et al, 2012). Specifically, he investigated the effects of autoantibodies against NMDA receptor in the context of synaptic plasticity and learning and memory, and autoantibodies mGluR1, in the context of synaptic remodeling and cerebellar ataxia. Pierre joined Prof. Gopal Thinakaran’s lab in 2014 as a post-doctoral fellow to work on AD. He became interested in the role of BIN1 in AD. BIN1 has been identified as the second most significant late-onset AD risk factor gene. Pierre has published two papers describing BIN1 physiological expression in the brain and its relation with tau tangles in the brains of patient with AD. In the Thinakaran lab, Pierre is now utilizing in vitro and in vivo models to understand BIN1’s function in the nervous system in health and disease.
I started working in neuroscience during my Master’s degree studies in France. I joined Pr. Honnorat’s lab because I was interested in the cellular biology of the synapses and their physiopathology. During my PhD studies, I had the chance to work on the description of a new regulator involved in synaptic plasticity, the cellular basis of learning and memory. I also had the opportunity to work on one pathological aspect of synapses, a disease known as limbic encephalitis. Limbic encephalitis, like Alzheimer’s disease (AD), is a serious condition responsible for memory and behavior trouble. These projects convinced me to pursue my career in the field of neuroscience, and sensitized me to the impact of brain pathologies.
For these reasons, after my PhD work, I decided to move to Chicago and join the Thinakaran lab to work on AD. For me, this was a new challenge and an opportunity to improve my knowledge in neurodegenerative diseases. I have benefitted greatly from the Thinakaran lab’s expertise in the area of AD cellular biology, and learned several techniques to develop original approaches. I started to work on BIN1, a newly-identified risk factor for late-onset AD. This project motivated me because very little is known about BIN1 function in the brain and its involvement in AD. I am currently exploring functions of BIN1 by generating mouse models to modify the levels of BIN1 expression in the brain, and investigating how altering the levels of this protein can modify AD-related pathophysiology.
This project funded by the BrightFocus Foundation is a great opportunity to make a significant step forward in the understanding of BIN1. With the Foundation’s support, I will be able to test new hypotheses, develop new models, and, eventually bring to the Alzheimer’s field important new knowledge on the role of BIN1 as a risk factor. In the future, my research could lead to the design of a new therapeutic strategy targeting BIN1.
De Rossi P, Nomura T, Andrew RJ, Masse NY, Sampathkumar V, Musial TF, Sudwarts A, Recupero AJ, Le Metayer T, Hansen MT, Shim HN. Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation. Cell Reports. 2020 Mar 10;30(10):3520-35. https://doi.org/10.1016/j.celrep.2020.02.026 PubMed ID: 32160554
De Rossi P, Andrew RJ, Musial TF, Buggia-Prevot V, Xu G, Ponnusamy M, Ly H, Krause SV, Rice RC, de l'Estoile V, Valin T, Salem S, Despa F, Borchelt DR, Bindokas VP, Nicholson DA, Thinakaran G. Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models. Brain Pathol. 2019 Jul;29(4):485-501. doi: 10.1111/bpa.12687. Epub 2018 Dec 27. PubMed PMID: 30506549; PubMed Central PMCID: PMC6542723<
Andrew RJ, De Rossi P, Nguyen P, Kowalski HR, Recupero AJ, Guerbette T, Krause SV, Rice RC, Laury-Kleintop L, Wagner SL, Thinakaran G. Reduction of the expression of the late-onset Alzheimer's disease (AD) risk-factor BIN1 does not affect amyloid pathology in an AD mouse model. J Biol Chem. 2019 Mar 22;294(12):4477-4487. doi: 10.1074/jbc.RA118.006379. Epub 2019 Jan 28. PubMed PMID: 30692199; PubMed Central PMCID: PMC6433054.
First published on: September 14, 2017
Last modified on: March 17, 2020