Dr. Sam S. Sisodia’s seed grant focuses on Alzheimer’s disease which is characterized by degeneration of the brain due to the accumulation of toxic peptides called Abeta peptides. Abeta is derived from a larger protein called amyloid precursor protein and is a normal product of cellular metabolism in the brain and other organs. However, when individual Abeta peptides accumulate to high levels, they can become toxic through aggregation into larger species called oligomers and finally into even larger entities known as fibrils. Both oligomers and fibrils are thought to disrupt the normal processing of the brain by interfering with cell-to-cell communication at the synapse and by causing dystrophy of cellular protusions called dendrites and axons through which they communicate with other cells. Thus, a key to combating Alzheimer’s is keeping levels of Abeta within the normal physiological range. This is a balance between production and clearance. One proposed Abeta “scavenger” is a protein called transthyretin (TTR) which exists in high levels in the cerebrospinal fluid and serum. Much evidence supports this theory, including preliminary evidence we have generated within our laboratory. Our goal to generate ordered crystals of TTR and Abeta in a complex so we can analyze the structure of this complex by passing X-rays through it. Understanding this structure will allow us (and the research and medical community at large) to develop strategies to remove Abeta efficiently so that normal levels may be reestablished in the brain.
Sangram Sisodia, Ph.D.