The objective of this proposal is to understand the causes of synaptic damage that is present in Alzheimer's disease (AD). Increasing evidence indicate that synapse loss is one of the earliest alterations and the best correlate of the cognitive deficits in AD. Consequently, it is crucial to understand what causes synaptic injury in AD, especially in the earliest or even pre-disease stages. Amyloid beta-protein, the major constituent of senile plaques in brain, has been shown to impair synaptic function both in vitro and in vivo. However, the mechanisms by which Abeta induce synaptic dysfunction and synapse loss are not clear. In this project, we will test several hypotheses of Abeta-induced synaptic damage in several animal models of AD-related pathology that share conceptual and technical approaches in common with the other three Projects of this Program. In the first Aim, we will determine whether Abeta released from the pre- or postsynaptic neuron is more important in Abeta induced synaptic dysfunction. This will be tested by selectively expressing amyloid precursor protein (APP) in CA1 or CAS neurons, respectively, and assessing the function of the synapses between these two sets of neurons.
The second Aim will examine how age influences Abeta induced synaptic dysfunction in hippocampal neurons. While most studies have concentrated on the effects of Abeta reduction in brain, our approach tests the opposite scenario: how long does Abeta exposure have to be sustained in brain before synaptic transmission is perturbed and whether this is related .toage. Lastly, if synaptic perturbations are indeed early and key contributors to neurodegeneration, then axons are likely to degenerate concomitantly. In this regard, axonal pathology is seen in brains of AD individuals and in animal models.
The third Aim will examine the phenotype of APP transgenic mice crossed to the WLDs (slow Wallerian degeneration) mutant mice. Axons in the latter mutant animals are protected in injury and from various toxic agents and neurodegeneration. Consequently, we can test whether preserving axons can attenuate synaptic damage in APP transgenic mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032179-02
Application #
7496385
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (J1))
Program Officer
Snyder, Stephen D
Project Start
2007-09-15
Project End
2012-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$321,324
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Midthune, Brea; Tyan, Sheue-Houy; Walsh, Jessica J et al. (2012) Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function. Mol Cell Neurosci 49:448-55
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