BIN1 as a Risk Factor in Tau Pathology in an Inducible Transgenic Model
Principal Investigator
Mentors
Project Goals
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.
Project Summary
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.
Publications
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: November 22, 2024