Project Summary
Alzheimer's disease (AD), a devastating neurodegenerative disease, is the most common form of dementia among older people. Aside from age, the greatest known risk factor for AD is the gene for one of three apolipoprotein (apo) E isoforms: apoE4. ApoE4 is associated with 40–60% of cases of AD. In contrast, apoE3 appears to offer some protection against AD, and apoE2 is even more protective. ApoE3 and apoE4 differ by only a single amino acid in their protein sequence. As a result of domain interaction, apoE4 has a more compact structure than the other forms of apoE, and this property likely contributes to its adverse effects in neurobiology. ApoE4 is also the least stable isoform of apoE, causing it to more readily form a molten globule state. Molten globules are associated with several pathological conditions. Since the structure of a protein often determines its function, an apoE4 molten globule is an intriguing potential mechanism to explain the pathological functions of apoE4 in various diseases. Dr. Zhong will aim to learn the correlation between apoE4 isoform-specific structural properties and synaptic pathology, one of the major manifestations of AD. The structural specificity of apoE4 suggests an intriguing strategy for developing AD therapies: convert apoE4 into a molecule that more closely resembles apoE3 or apoE2.