The abnormal accumulation of ?-amyloid (A?) in the brain is believed to play a pivotal role in the etiology and pathogenesis of Alzheimer's disease (AD). A? is produced continuously in the brain, but under normal circumstances its accumulation is prevented by its rapid catabolism. Compared to the breadth of knowledge concerning the enzymes and pathways involved in A? production, relatively little research has been devoted to understanding A? removal. Two lines of evidence indicate that endothelin-converting enzyme (ECE)-2 is an A? degrading enzyme that regulates steady-state levels of the peptide in the brain, and that alterations in its activity potentially contribute to AD pathogenesis. First, we have shown that the steady-state levels of endogenous A? are increased in the brains of mice deficient in ECE-2, similar to that observed in animals transgenic for AD-causing presenilin mutations. Second, ECE2 has been shown to be the single most down- regulated gene in AD brain by microarray analysis. Based on these data, our working hypothesis is that alterations in ECE-2 activity influence AD pathogenesis. We will test this hypothesis in three interrelated Aims that examine the ability of ECE-2 to directly degrade A? in vitro and promote alterations in pathology in vivo in animal models. In addition, we will examine ECE-2 expression in our large series of brain tissue from autopsy- confirmed AD cases and age-matched controls and identify and analyze genetic variants in ECE2 to determine whether these correlate with alterations in gene expression and susceptibility to late-onset AD (LOAD).

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS073512-05
Application #
8694106
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Atlantic Health System, Inc.
Department
Type
DUNS #
City
Morristown
State
NJ
Country
United States
Zip Code
07960
Barnwell, Eliza; Padmaraju, Vasudevaraju; Baranello, Robert et al. (2014) Evidence of a novel mechanism for partial ?-secretase inhibition induced paradoxical increase in secreted amyloid ? protein. PLoS One 9:e91531
Pacheco-Quinto, Javier; Herdt, Aimee; Eckman, Christopher B et al. (2013) Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease. J Alzheimers Dis 33 Suppl 1:S101-10
Pacheco-Quinto, Javier; Eckman, Elizabeth A (2013) Endothelin-converting enzymes degrade intracellular ýý-amyloid produced within the endosomal/lysosomal pathway and autophagosomes. J Biol Chem 288:5606-15