The LDL receptor-related protein (LRP) family is of interest in Alzheimer disease (AD) research because it includes several receptors for apolipoprotein E (ApoE), and polymorphisms in the gene for the latter (APOE) create the most demographically significant genetic risk factor for developing AD. Another genetic contribution is made by the genes for presenilins (PS)-1 and - 2;mutations in these genes are responsible for the largest fraction of early-onset AD inherited in an autosomal-dominant manner. Preliminary data indicate that such PS1 mutants reduce the steady-state levels of LRPs below what is seen with wild-type PS1. The proposed studies will characterize this relationship further and test the mechanisms involved and the consequences for LRP function. Successful completion of these studies will inform a novel hypothesis that places LRP dysfunction at a central point in the mechanisms common to AD pathogenesis.

Public Health Relevance

Alzheimer's disease appears to develop through processes that involve apolipoprotein E (ApoE), as polymorphisms in its gene dramatically affect the risk of developing Alzheimer's. Prior studies indicated that a family of receptors that bind ApoE, the LRP family, is influenced by an enzyme called gamma-secretase. This enzyme involves the presenilin proteins, which also have a genetic link to Alzheimer's disease. The proposed research will test the hypothesis that the amount of LRP-family proteins present in cells of the brain is reduced by mutant forms of the presenilins. Confirmation of this hypothesis will justify larger future projects that seek to integrate this idea into a more comprehensive, novel theory which supposes that LRP dysfunction is responsible for the initiation and progression of most cases of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Type
Small Research Grants (R03)
Project #
5R03AG043784-02
Application #
8741904
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205