The ?4 allele of apolipoprotein E (apoE4) is the most important genetic risk factor for late-onset sporadic Alzheimer's disease (LOAD). ApoE is a secreted glycoprotein that binds to a number of single-pass transmembrane receptors of the low-density-lipoprotein receptor family, including apoER2 (official gene name = LRP8). Interestingly, human apoER2 is subject to a high degree of alternative splicing events and notably one of the top 10 of all neuronal genes related to exon-skipping splicing events. We have identified and confirmed the expression of a large number of alternatively spliced apoER2 receptors in human brain, many of which contain a different number of ligand binding domains which alter the binding of human apoE protein to apoER2. However, the functional consequences of differential apoE-apoER2 interactions, downstream receptor signaling and neuronal function for these naturally occurring human apoER2 splice variants remain incompletely understood. The goal of this proposal is to define the functional consequences of specific apoE- apoER2 interactions that could have major implications for our understanding of synaptic plasticity associated with learning and memory and the role of apoE4 in LOAD.

Public Health Relevance

The ?4 allele of apolipoprotein E (apoE4) is the most important genetic risk factor for late-onset Alzheimer's disease (AD) and functionally binds to receptors of the LDL receptor family including apolipoprotein E receptor 2 (apoER2) which is highly expressed and found as multiple alternatively spliced variants in human brain. However, the functional significance such as apoE ligand binding, downstream receptor signaling and neuronal function of these naturally occurring human apoER2 splice variants remains incompletely understood. The goal of this proposal is to define the functional mechanisms of specific ligand-receptor (apoE-apoER2) interactions which could have major implications for our understanding of learning and memory and how it affects AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG059762-01
Application #
9579539
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Dibattista, Amanda
Project Start
2018-08-01
Project End
2023-06-30
Budget Start
2018-08-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code