Structure of Abeta C-Terminal Domain in Toxic Oligomers
The seminal event in Alzheimer's disease is the misfolding and clumping of a protein fragment into small particles that are highly toxic to brain cells. Why such peptide particles are toxic, while other particles composed of the same peptide are non-toxic, is one of the key unanswered questions in Alzheimer's disease research. We seek to explain the structural differences between toxic and non-toxic peptide particles with the long-term goal of guiding the rational design and development of new therapeutics to treat Alzheimer's disease.
A protein called amyloid precursor protein (APP) can be cut into toxic and non‐toxic forms of beta‐amyloid. The toxic forms of beta‐amyloid (called beta‐amyloid 42) misfold and clump together into brain plaques, a hallmark of Alzheimer's disease. Other beta‐amyloid fragments of APP do not misfold. Dr. Peter Tessier and collaborators will use new detection methods to study the differences between toxic and non‐toxic folding of beta‐amyloid proteins in Alzheimer's disease. Their long term goal is to design a drug that could prevent this folding and clumping. If successful, this method could be applied to toxic misfolding that happens in other neurodegenerative diseases, like Parkinson's disease, Huntington's disease, and Prion disease (including Creutzfeldt-Jakob or “Mad Cow” disease).