Herpes simplex virus type 1 (HSV-1) is latent in the trigeminal ganglia (TG) of most people. HSV-1 can also be latent in the human brain. Our hypothesis is that during the lifetime of a latently infected person, the combination of repeated neuronal reactivations of HSV-1 and the presence of a genetic factor, Apolipoprotein E (ApoE) allele e4, leads to chronic cerebral inflammation, neuronal degeneration, and an increased risk of Alzheimer's disease (AD). Our research team will test this hypothesis using autopsy specimens from a repository of 1,266 cases containing neuropathologically confirmed AD or cognitively normal patients.
The Specific Aims are:
Aim 1 : (A) Quantitate HSV-1 DNA in AD and normal brain in 8 brain regions [entorhinal cortex, hippocampus, pons, cerebellum, and neocortex (temporal, parietal, occipital, and frontal)] that are known to exhibit varying degrees of AD lesions. The presence and genome copy numbers of HSV-1 DNA will be determined in these 8 brain regions and a newly developed Neuroinvasive Score will be used to assess the HSV-1 phenotype for each patient. Neuroinvasive Scores will range from 0 (no HSV-1 DNA in TG or any brain regions) to 9 (HSV-1 DNA in TG and all 8 brain regions). We have new evidence that HSV-1 DNA can be quantitated in specific brain regions. (B) Compare the neuropathological severity (tangles and plaques) to the Neuroinvasive Score. Since AD pathology generally exhibits bilateral symmetry, we will analyze tissue from one side of the brain by quantitative morphometric neuropathological methods and employ quantitative analytical methods to measure the HSV-1 DNA and HSV-1 RNA in the opposite hemisphere. (C) Determine the relationship between the Neuroinvasive Score and the presence of ApoE e4, relative to the occurrence of AD.
Aim 2 : (A) Quantify the HSV-1 latency-associated transcripts (LAT) in tissues positive for HSV-1 DNA. We have new evidence that HSV-1 LAT can be quantitated in human brain regions. (B) Detect and quantitate HSV-1 mRNAs in tissues positive for HSV-1. This project could lead to strategies to identify high-risk individuals who would be treated with antivirals, thus reducing their risk of developing AD. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023085-04
Application #
7284199
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Snyder, Stephen D
Project Start
2004-09-30
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2007
Total Cost
$165,610
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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Hill, James M; Zhao, Yuhai; Clement, Christian et al. (2009) HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling. Neuroreport 20:1500-5

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