Alzheimer’s disease

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.

Other Grants

Lindsay M. De Biase, Ph.D., University of California Los Angeles
The Role of Microglial Lysosomes in Selective Neuronal Vulnerability
Synapses, the sites of signaling between neurons in the brain, play essential roles in learning, memory, and the health of neurons themselves. An enduring mystery is why some neurons are…
How the Nervous System Constructs Internal Models of the External World
As animals navigate their environments, they construct internal models of the external sensory world and use these models to guide their behavior. This ability to incorporate ongoing sensory stimuli into…
Xiaojing Gao, Ph.D., Stanford University
When Neural Circuits Meet Molecular Circuits: Quantitative Genetic Manipulation with Single-cell Consistency
Cells are the building blocks of our bodies. We get sick when the cells “misbehave”. The way modern gene therapies work is to introduce genes, fragments of DNA molecules that…
Rafiq Huda, Ph.D., Rutgers University
Conducting the Orchestra of Movement—Functional Role of Striatal Astrocytes in Health and Disease
Movement requires coordinated activity across a large brain-wide network. The striatum is a particularly important part of this circuit; it integrates motor-related information from many distinct brain regions to regulate…