The Role of Lysosomes in Beta-Amyloid Mediated Neurotoxicity

The Aß is a peptide that constitutes the major protein component of senile plaques in brains of Alzheimer’s disease patients. The Aß peptide is derived from a larger brain precursor protein, named amyloid precursor protein (APP) and this protein is normally processed in a special way which would prevent this protein become Aß peptide. It is generally believed that the abnormal processing of APP inside the brain causes the initial buildup of amyloid deposits which then trigger the death of brain cells. Recently, we have chemically synthesized several Aß analogs, and found that Aß1-42, corresponding to one of the longer forms of the A4/ß protein, accumulates inside the cultured human cells and is concentrated within a cellular compartment known as lysosome which is responsible for digesting proteins such as APP inside the cell. Since the abnormal function of lysosomes has been directly related to the accumulation of Aß in Alzheimer’s disease and other neural degeneration, we decide to examine the effect of Aß1-42 aggregates on the processing of APP in cultured cells. Our preliminary data indicate that the intracellular Aß1-42 aggregates cause a dramatic increase in the amount of incomplete digested APP fragments which have been described in cultured neurons and brains of Alzheimer’s disease patients. This observation suggests that the presence of Aß aggregates could establish a new pathway for APP metabolism and lead to the long term stability of the fragments which are resistant to degradation. The toxicity of this protein to neurons may also be related to the inability of cells to get rid of it. This research grant is an attempt to extend the previous study and test whether there is a direct lysosomal damage caused by the incubation of cultured cells with synthetic Aß. If aggregation of Aß is important for acquiring it resistance to degradation inside the lysosomes, agents that interfere with aggregation may be rational targets for the development of therapeutic agents that prevent amyloid accumulation. In addition, we will also attempt to isolate genes that may play an important role in Aß mediated lysosomal dysfunction in degenerative neurons. The ability to identify these new genes and evaluate their role in response to cell death would represent potential new directions for future research. In conclusion, we believe we have reproduced some of the pathophysiology conditions that are similar to the early disease states of Alzheimer’s disease and aged brains in cultured cells. The non-animal culture system, therefore, could be a useful tool to study the factors leading to the accumulation of amyloid and Iysosomal pathophysiology that has been associated with Alzheimer’s disease.