Early-onset familial Alzheimer's disease is the most aggressive form of Alzheimer's, striking patients as early as their 30s; Those patients, typically carrying mutations in presenilin-1 (PS1) and presenilin-2 (PS2), exhibit accelerated onset of memory loss and dementia, progressive impairments in problem solving, language, and other cognitive abilities. Their brains are usually hallmarked by accumulations of senile plaques and neurofibrillary tangles, selective shrinkage of cortical and hippocampal tissues, and enlargement of lateral and third ventricle volume. Since conventional knockout of both PS1 and PS2 leads to early embryonic lethality which unfortunately prevents the analysis of their in vivo function in the adulthood, the role of presenilins and their coordinated interactions in adult brain is not known. Moreover, mutations in the presenilins are nearly all missense mutations; this has led to the popular notion that a """"""""gain-of-function"""""""" mechanism may be the leading explanation for the molecular pathogenesis of the early-onset AD. In this proposal, we set to examine the hypothesis that both PS1 and PS2 are critically involved in maintaining the adult brain structure and function. We propose to use conditional knockout technique to study the relationship of presenilins, apoptosis, and brain degeneration. The first major set of experiments will focus on the production and basic characterization of the conditional double knockout mice. The second major set of experiments will be conducted to examine whether and how the deletion of both presenilins leads to increased apoptosis and degeneration of adult forebrain. Understanding the role of presenilins in the adult brain may provide us with new avenues to delay or prevent the pathogenesis of brain degenerative disease during ageing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025918-02
Application #
7097910
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Wise, Bradley C
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2006-07-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$323,295
Indirect Cost
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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