Structural and Functional Analysis of Novel Abeta and Tau Oligomers Using Conformation-Specific Monoclonal Antibodies

The goal of this project is to determine which oligomers of Abeta and Tau are most damaging and whether specific antibodies can prevent formation of those oligomers.

Two types of abnormal structures, amyloid plaques and neurofibrillary tangles, have long been known to accumulate in the brains of Alzheimer’s disease (AD) patients, but recent advances point to the building blocks of these structures as the actual disease-causing agents. The building blocks of plaques are small clusters, or “oligomers” of Abeta peptides, which represent small pieces of a larger protein and are aggregated into densely packed, insoluble fibers in the plaques. Tangles arise by an analogous process and also comprise densely packed, insoluble fibers, but their building blocks are oligomers of the protein known as Tau. There are many structurally distinct versions of both Abeta and Tau, and the oligomers they form vary in size and shape. It follows naturally that development of procedures for early diagnosis and effective treatment of AD depend on learning exactly which oligomers of Abeta and Tau are most damaging.

This project builds on recent discoveries made in the labs of Dr. George Bloom at the University of Virginia and Dr. Charles Glabe of the University of California, Irvine. Bloom’s lab identified a new class of exceptionally toxic Abeta oligomers that are self-propagating, like the infectious particles that cause mad cow disease, and they also have been studying how Abeta oligomers can seed formation of Tau oligomers. Concurrently, the Glabe lab developed a new and intriguing collection of antibodies that were made by immunizing rabbits with Abeta. Collectively, these antibodies stain a variety of abnormal structures in post-mortem brain tissue removed from the brains of AD patients and mice that are genetically engineered to develop AD. Most notable among these structures are “aggrodegrosomes,” or “ADsomes,” which were seen in the human tissue, had never been observed earlier and represent a brand new type of brain lesion associated with AD. Remarkably, several of the Glabe lab antibodies recognize multiple proteins in addition to Abeta. We will see if any of the Glabe lab antibodies recognize the Abeta or Tau oligomers that the Bloom lab is studying, and whether the antibodies can prevent formation of those oligomers. Completion of this work could lead eventually to new diagnostic and therapeutic tools for AD.