Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. An important component of AD pathology relates to the accumulation of amyloid plaques in the brain. Recent genome scans have identified ten novel AD susceptibility loci, and several of these loci implicate the immune system in late-onset AD. CD33 is one of these genes;the protein is a transmembrane glycoprotein expressed on the surface of myeloid progenitor cells and mature monocytes and appears to have a constitutive repressor function, subduing monocyte pro- inflammatory cytokine production. Interestingly, our preliminary data shows a strong correlation of increased CD33 expression on monocytes and the CD33 risk alele. Determining the role that altered CD33 expression plays in the basic functions of monocytes, will give important insights into the potential role of this molecule in AD pathology. Using three different collections of human subjects, we will characterize the functional consequences of the CD33 locus in monocytes in (1) younger healthy subjects (2) presymptomatic older subjects, and (3) subjects with AD. We propose a multifaceted approach integrating human genetic and human immunology experiments throughout the life course to understand how the CD33 locus alters the state of activation in monocytes and enhances susceptibility to AD. !

Public Health Relevance

This project is of direct relevance to Alzheimer's disease, as we are studying monocytes and microglia from patients with Alzheimer's disease, pre- symptomatic older subjects and young subjects, many of whom will develop Alzheimer's disease in later life. Our data will potentially provide a mechanism of how a region of the human genome containing the CD33 gene alters the function of the immune system and in doing so, increases an individual's risk of developing Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG043617-03
Application #
8661677
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Petanceska, Suzana
Project Start
2012-09-30
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$349,197
Indirect Cost
$109,429
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Raj, Towfique; Ryan, Katie J; Replogle, Joseph M et al. (2014) CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer's disease susceptibility. Hum Mol Genet 23:2729-36