Recently studies have suggested that amyloid precursor protein (APP) plays a major role in synaptic plasticity. In Alzheimer's disease (AD), APP is abnormally accumulated in aberrant sprouting neurites in the plaque. Furthermore, APP is localized in the synaptic apparatus and, depending on the dosage, it promotes neuritic outgrowth, synaptogenesis and neuronal survival in vitro and in vivo. Therefore, we hypothesize that a mutation in the APP gene (or a related gene) represents a predisposing condition which, in combination with adjuvant factors (eg. ischemia, aging, trauma), triggers the development of the disease. Ischemia, aging and trauma are conditions known to be associated with synaptic loss. If APP is involved in mechanisms of synaptic repair and plasticity, altered APP might lead to an abnormal reparative response and accentuation of synaptic damage. For the present project, we propose to analyze the patterns of synaptogenesis and sprouting in the brains of transgenic (tg) mice into which the human APP gene has been introduced, and that later in life received a nervous system injury (ischemia, denervation). In order to analyze the effect of these conditions on the synaptic organization of the brain, sections double-immunolabeled for APP/synaptophysin/GAP-43 will be studied with the aid of laser scanning confocal microscopy and computer aided image analysis. The following lines of mice will be analyzed at different ages: a) tg with neuron specific enolase (NSE) promoter-APP751 construct (with no mutation), b) tg with NSE-APP751 construct (with Hardy's mutation in 717), c) tg with NSE-APP695 (no mutation), d) tg with NSE-APP695(with G->A mutation), and e) corresponding non-transgenic (non-tg) controls. Groups of tg and non-tg animals will receive either entorhinal cortex lesion, global ischemia, or kindling. The information derived form this study will provide important data as to the role of APP in plasticity and could help to understand the mechanisms of synaptic pathology in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005131-15
Application #
6267253
Study Section
Project Start
1998-04-15
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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