Role of APP and Abeta-induced synaptic dysfunction
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.
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.