Biochemical and Crystallographic Characterization of Abeta in Complex With Transthyretin – A
Proposed Abeta Scavenger
2008 Seed Grant
Sangram Sisodia, Ph.D.
University of Chicago
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.