Autosomal dominant inheritance of mutations in PS1 and PS2 cause early-onset familial forms of AD. A series of neuropathological studies of humans and transgenic mice expressing FAD-linked PS1 have revealed that these mutant polypeptides likely cause AD by elevating production of amyloidogenic AB42 (43) species, thus fostering AB deposition. Despite the strengths of these conclusions, it is not clear that FAD-linked mutant PS1 exerts pathophysiological effects solely by promoting deposition of AB peptides. We propose investigations that address the function of PS1 and FAD-linked PS1 variants in neuronal physiology that are independent of AB42 production and deposition.
In Specific Aim 1, we propose a series of electrophysiological, pharmacological and imaging studies in cultured neurons from wt and PS1-deficient mice to identify the mechanism(s) that underlie our observations that PS1 influences glutamatergic neurotransmission at both pre-and post-synaptic sites.
In Specific Aim 2, we propose electrophysiological studies in hippocampal slices from transgenic mice expressing wt or FAD-linked mutant PS1 to assess the mechanism(s) underlying our demonstration that expression of mutant PS1 potentiates long-term potentiation (LTP) at Schaffer collateral CA1 synapses. In addition, we will examine LTP in hippocampal slices from mice with selective forebrain ablation of PS1, using a conditional gene knockout strategy.
In Specific Aim 3, we propose to test the hypothesis that expression of mutant PS1 alters the threshold for vulnerability to lesion-induced excitotoxicity, or other insults. For these studies, we will exploit a perforant path lesion paradigm to examine neuronal vulnerability in the entorhinal cortex of mice expressing wt or FAD-linked mutant PS1. In addition, we will extend our intriguing observation that dentate neurogenesis is markedly elevated following perforant path lesions and examine the influence of PS1 and mutant PS1 in these processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG021494-01
Application #
6559473
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (O1))
Program Officer
Snyder, Stephen D
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$387,294
Indirect Cost
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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