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Jeffery W. Kelly | |
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The amyloid β-peptide (Aβ) is a 39- to 43-residue polypeptide that is formed by proteolytic processing of a 770-residue trans-membrane precursor protein. The process of Aβ amyloidogenesis (Figure 1) appears to cause Alzheimer's disease based on biochemical and genetic evidence. Some cases of early onset Alzheimer's disease are associated with mutations that alter the sequence of Aβ or affect the processing of the precursor protein resulting in a higher concentration of longer and more amyloidogenic sequences of Aβ being produced. However, the vast majority of Alzheimer's disease cases are sporadic, not associated with any known mutations. Therefore, the occurrence of Alzheimer's disease in some individuals but not others is difficult to explain, because factors other than known mutations may initiate or enhance the formation of Aβ fibrils.
Inflammation is associated with the early stages of Alzheimer's disease. Reactive oxygen species produced during inflammation (during for instance a viral infection or an injury), including ozone, superoxide and hydroperoxides, can convert normal metabolites (e.g. cholesterol, arachidonic acid and unsaturated lipids) into highly reactive metabolites. These oxidative metabolites contain functional groups (e.g. aldehydes) that covalently modify proteins and alter their physical properties, especially natively unfolded proteins like Aβ and α-synuclein, the latter being associated with Parkinson's disease. In collaboration with Dr. Lerner and Dr. Wentworth (The Scripps Research Institute, Department of Chemistry), we discovered a new class of aberrant metabolites originating from cholesterol ozonolysis that exist in human brains. We found that these and other metabolites covalently modify Aβ, greatly increasing its amyloidogenicity. This increase is caused by both thermodynamic factors, in that the minimum peptide concentration required for amyloid formation is reduced, and kinetic factors, in that amyloid formation becomes much faster. These findings suggest that metabolite-initiated Aβ amyloidogenesis may contribute to the onset of sporadic Alzheimer's disease, representing the majority of the cases. Antioxidants and complementary strategies that prevent metabolite-initiated misfolding are being sought for Alzheimer's disease.
We seek to understand the structures of Aβ resulting in toxicity in tissues, and the roles that metabolites and catabolism (turnover) play in pathology. We are also interested to design immune strategies against Alzheimer's disease.
