Associate Provost for Research Boston University Medical Campus
NIA - National Institute on Aging	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): 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.

Thesaurus Terms:
Alzheimer's disease, aging, apoptosis, disease /disorder model, disease /disorder onset, frontal lobe /cortex, laboratory mouse, neural degeneration, neurogenetics, neuropathology, presenilin
gene mutation, genetic disorder, molecular pathology, neurofibrillary tangle, neurogenesis, prosencephalon, tau protein
genetically modified animal, immunocytochemistry

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2006
Department:	PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Project Start:	01-AUG-2005
Project End:	31-MAY-2010
ICD:	NATIONAL INSTITUTE ON AGING
IRG:	NDBG