BrightFocus Foundation
BrightFocus Foundation

Metabolomic/Lipidomic Analysis of ApoE Isoform Effects

Principal Investigator

Tal Nuriel, PhD

Tal Nuriel, PhD

Columbia University Medical Center
New York, NY
Acknowledgement
This grant is made possible in part by a bequest from the Louise T. Baker Trust.

Co-Principal Investigator

Mentors

Project Goals

The apolipoprotein E (apoE) gene controls a small protein that helps clear cholesterol and other fats though the bloodstream. For some time, Alzheimer’s researchers have focused on a variation of the apoE gene known as the “E4” allele. Carriers of the apoE4 mutation are at significantly increased risk for developing late-onset Alzheimer’s disease. In order to understand the cause of this increased Alzheimer’s risk, we will utilize emerging technology to measure the levels of lipids and small-molecules in mouse and human brain tissues possessing differing forms of apoE. We anticipate that the results of this study will shed new light on why apoE4 carriers are more susceptible to Alzheimer’s disease and how Alzheimer’s disease can be prevented in these individuals.

Project Summary

The goal of this project is to discover new molecules that are affected by expression of the apoE4 gene and that may play a role in the increased risk of Alzheimer’s disease among apoE4 carriers.

In order to do this, we will use emerging technology known as “omics” to identify lipids and small molecules in the brain that are affected by the expression of differing forms of apoE. Using this technology, we will be able to observe hundreds of lipids and thousands of small-molecules in order to identify the specific molecules that either increase or decrease when different forms of apoE are expressed. We will then utilize additional biochemical techniques to discover whether these changes are involved in the increased risk for Alzheimer’s disease that occurs among apoE4 carriers.

This project will be the first to utilize multiple versions of this “omics” technology to investigate the potential mechanisms responsible for the link between apoE4 and Alzheimer’s disease. Importantly, we anticipate that the results of this study will not only shed light on the role of apoE4 in Alzheimer’s disease, but may also point to previously undiscovered processes involved in the development of Alzheimer’s disease.

Although numerous clinical trials for Alzheimer’s disease are currently under way, most are aimed at preventing or eliminating the two main hallmarks of Alzheimer’s disease, amyloid plaques and neurofibrillary tangles. By uncovering new processes involved in the increased risk of Alzheimer’s disease among apoE4 carriers, we hope that this study will identify new therapeutic targets that will increase our chances of finding a successful treatment for Alzheimer’s disease in the near future.

Publications

Area-Gomez E, Larrea D, Pera M, Agrawal RR, Guilfoyle DN, Pirhaji L, Shannon K, Arain HA, Ashok A, Chen Q, Dillman AA, Figueroa HY, Cookson MR, Gross SS, Fraenkel E, Duff KE, Nuriel T. APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice. Sci Rep. 2020 Mar 9;10(1):4277. doi: 10.1038/s41598-020-61142-8. PubMed PMID: 32152337. PubMed Icon Google Scholar Icon

Nuriel T, Angulo SL, Khan U, Ashok A, Chen Q, Figueroa HY, Emrani S, Liu L, Herman M, Barrett G, Savage V, Buitrago L, Cepeda-Prado E, Fung C, Goldberg E, Gross SS, Hussaini SA, Moreno H, Small SA, Duff KE. Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology. Nat Commun. 2017 Nov 13;8(1):1464. doi: 10.1038/s41467-017-01444-0. PMID: 29133888; PMCID: PMC5684208. PubMed Icon Google Scholar Icon

First published on: July 09, 2014

Last modified on: April 29, 2024