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Alzheimer's Disease Research
Completed Award

Photo Pending

Sheue-Houy Tyan, Ph.D.

University of California, San Diego
La Jolla, CA

Title: Role of APP and Abeta-induced synaptic dysfunction
Non-Technical Title: The cause of Alzheimer's disease

Duration: April 1, 2010 - March 31, 2013
Award Type: Pilot
Award Amount: $150,000

Summary:

In this project, we are using the recently generated BRI-amyloid beta42 transgenic mouse line that offers the unique opportunity to examine amyloid beta-induced synaptic changes in the absence of APP over-expression. The study will provide insights into the potential causes of synaptic dysfunction in Alzheimer's disease.

Details:

It's essential to understand the cause of disease in order to develop specific treatments. The accumulation of amyloid beta within plaques in the Alzheimer's disease brain is a hallmark of Alzheimer's disease. More recently however, this "Amyloid Hypothesis" of Alzheimer's disease has been revised by many to account for the growing body of evidence suggesting the importance of effects at the junctions between nerve cells, or synapses. Moreover, much evidence has shown that there is a component of amyloid beta toxicity that is dependent on APP for the formation of APP complexes. Although the evidence that amyloid beta42 alters synaptic function and damages synapses is compelling, there are many crucial details that are unknown.

Many varied mechanisms have been proposed for amyloid beta42-induced synaptic damages, amyloid beta-APP interaction is one of the potential mechanisms that may contribute to neuronal degeneration in Alzheimer's disease. However, it is still unclear whether amyloid beta42 alone or its interaction with APP may play a central role on synaptic dysfunction of Alzheimer's disease in the current over-expressed APP transgenic animal model. In this study, we propose that using mice expressing amyloid beta42 (BRI-amyloid beta42) crossed with APP null-mice to determine the cause of synaptic damage in Alzheimer's disease and to provide new insight into the development and the treatment for Alzheimer's disease.

Therefore, one aim of this study, is to revisit this issue but focusing on the more relevant acute amyloid beta42 effects on synaptic phenotype rather than cell death as an endpoint. Further, in the second aim,this BRI-Abeat42 mice are crossed with APP deficient mice to test the hypotheses regarding (1) the specific contribution of amyloid beta42 peptide to the synaptic phenotype seen in Alzheimer's disease mouse models and (2) the dependency of these changes on endogenous amyloid pathology in vivo.

In this study, this hypothesis will be tested both in vitro and in vivo using the recently generated BRI-amyloid beta42 transgenic mouse line that offers the unique opportunity to examine amyloid beta-induced synaptic changes in the absence of APP over-expression. The study will provide insights into the potential causes of synaptic dysfunction in Alzheimer's disease.

Publications:

Midthune, B., Tyan, S.H., Walsh, J.J., Sarsoza, F., Eggert, S., Hof, P.R., Dickstein, D.L., Koo, E.H., 2012. Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function. Mol Cell Neurosci 49, 448-455. PubMed Icon Google Scholar Icon

Sheue-Houy Tyan, Ann Yu-Jung Shih, Jessica J. Walsh, Hiroko Murayama, Floyd Sarsoza, Lawrence Ku, Simone Eggert, Patrick R. Hof, Edward H. Koo and Dara L. Dickstein.  2012.  Amyloid precursor protein (APP) regulates synaptic structure and function. Molecular and Cellular Neuroscience, submitted (revision).

Progress Updates:

For Aim 1, Dr. Tyan’s team has tested the APP-dependent hypothesis of Abeta42-induced synaptic toxicity in cultured hippocampal neurons nerve cells and in acute hippocampal (brain) slices. The team has confirmed their preliminary findings that APP-deficient neurons are more resistant to Abeta42-induced synaptic loss, and that neurons missing APLP2 are more sensitive to Abeta42-induced synaptic loss. The results strongly supports the team’s hypothesis that there is an APP-dependent pathway in Abeta42-induced synaptic toxicity.

The team’s hypothesis will be tested further using the recently generated BRI-Abeta42 mice that offers the unique opportunity to examine amyloid beta-induced synaptic changes in the absence of APP overexpression. The team has bred the BRI-Abeta42 mice with mice lacking APP and let their offspring grow to either 2-4 months (young age) or 12 months (old age), for testing. Currently, they are examining the nerve cell synaptic structures in these young and old mice by immunostaining (that is, using a labeled antibody to identify the presence or absence, and location) of two synaptic proteins, called synaptophysin and PSD-95. In addition, they will examine the long-term potential (LTP) memory abilities of these mice. When completed, these studies will allow the team to test hypotheses regarding (1) the specific contribution of Abeta42 to the health of nerve cell communication through structural changes to their synapses, and (2) the dependency of these changes on the level of expression of APP. Taken together, their results should provide new insights into the mechanisms of Abeta42-induced synaptic toxicity.

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