Cellular and Animal Models of Amyloid Pathology in Early Alzheimer’s Disease

The goal of this project is to evaluate the pathological significance of a new type of Abeta deposits in the brain (at the onset of Alzheimer’s disease) in order to develop a novel mechanism for amyloid pathogenesis to help convince the FDA to approve and support early clinical trials.

Although the genetics of Alzheimer’s disease (AD) implicates Abeta as a causal agent of pathology, the potential mechanisms of amyloid pathology are numerous, and there is no consensus about which mechanisms are critically important. The simple formulations of the “amyloid hypothesis” have a number of weaknesses, including the fact that amyloid plaques do not correlate well with disease and that cognitively normal individuals can have the same amount of plaque amyloid as patients with dementia. This has led to a reformulation of the amyloid hypothesis where other types of amyloid aggregates, such as soluble oligomers, are postulated to be the primary pathogenic species. If this is the case, there is considerable disagreement about which specific oligomers are toxic and why they are pathological. Dr. Charles Glabe’s previous work established that Abeta can form a variety of structurally and immunologically different types of oligomers. In work that was partially funded by Cure Alzheimer’s Fund, he and his team have recently produced a battery of monoclonal antibodies by immunizing rabbits with Abeta. The goal of this effort was to obtain as many different antibodies as possible with the hope they might reveal new types of amyloid aggregates in the brain. Most of these antibodies are conformation dependent and specifically recognize Abeta aggregates and not Abeta monomer or the amyloid precursor protein, APP. One of these antibodies, Mab78, identified a new type of Abeta pathology in an aged human and AD brain. Analysis of more than 20 different human brain samples suggests this new pathological accumulation of Abeta is a very early event in aging of AD pathogenesis and disappears as plaques accumulate in later stages of AD.

In order to experimentally evaluate this relationship and the pathological significance of this new type of Abeta deposits, researchers need a living system they can study over time and manipulate experimentally. The potential significance of this work may be the identification of the earliest type of amyloid pathology at the onset of the disease and the discovery of a novel mechanism for amyloid pathogenesis. This may provide a new target for therapeutic development and provide evidence for the early initiation of the disease before cognitive impairments. This evidence could be instrumental in convincing the FDA to approve and support early clinical trials, which may have a much better chance of preventing or curing the disease.