Compelling genetic evidence links the principal component of amyloid plaques, the amyloid beta-protein (Abeta), to Alzheimer’s disease (AD). However, clinical trials of Abeta-targeting agents have proved disappointing and there is lingering concern about the relevance of Abeta to AD causation. Unlike agents in other conditions, there is no robust connection between fibrillar Abeta pathology and disease, i.e. plaque density and number poorly correlate with the presence and severity of disease. An explanation for this apparent lack of pathological cause and effect is that histologically-invisible soluble forms of Abeta, loosely referred to as “oligomers”, are the primary mediators of neurotoxicity. While numerous studies indicate that oligomers formed in vitro have toxic activity, surprisingly little effort has been devoted to analyzing bioactive forms of brain-derived Abeta. Research by the PI has demonstrated that water-soluble Abeta (WS-Abeta) extracted from AD brain can alter synaptic structure and function when applied to cultured neurons or injected into the brains of rodents. The objective of this project is to determine whether toxic brain Abeta species really do cause AD. Put simply, if Abeta is the initiator of a pathogenic cascade that causes AD, then it follows that a person cannot develop AD without being exposed to significant levels of WS-Abeta. Similarly, an individual would rarely have appreciable amounts of WS-Abeta without having the disease. Hence a test of the causal role of Abeta can be approached in a single large-scale experiment, i.e. to measure the levels of WS-Abeta in the brains of individuals who died in early/moderate stage AD vs. those who died free of AD. If WS-Abeta causes AD, we should detect abundant bioactive material in the AD brain but little or none in the brains of cognitively normal humans.
While the principle of this approach is straightforward, the practicalities are potentially challenging. First, how do we overcome the confounding possibility that the non-demented group may be “contaminated” by cases of incipient AD? Second, how do we control for material artefactually released from plaques? In regard to the first question, recent longitudinal studies on patients with mild cognitive impairment and individuals with dominantly inherited forms of AD indicate that CSF biomarkers can accurately predict onset of AD 5-10 years in advance. Thus we plan to measure CSF biomarkers to confirm the authenticity of our diseased and disease-free samples and then test if the levels of WS-Abeta really segregate with disease. The second issue can be controlled for by utilizing tissue from non-demented, biomarker-negative individuals that have abundant amyloid pathology.
In this project we will also classify and document the types of amyloid deposits so as to understand if there is a link between the presence of certain types of amyloid deposits, WS-Abeta and the presence of AD-type dementia. Understanding this link should hasten the development of better disease biomarkers and facilitate the development of novel therapeutics designed to target water-soluble Abeta. As part of this effort the MD student will prepare and analyze homogenates from the brains of non-demented controls and individuals who died of AD. Analysis will involve the use of a variety of standard biochemical and immunological techniques including: ELISA, sedimentation analysis, size exclusion chromatography, immunoprecipitation and Western blotting. The student will have the opportunity to work as part of a team which will include a postdoctoral protein biochemist, a neuropathologist and the PI.

The subtlety and variability of the earliest amnestic symptoms of Alzheimer disease (AD) indicate that something is discretely and intermittently interrupting the function of synapses that encode new declarative memories. A wealth of findings now suggests that this “something” is the amyloid beta-protein (Abeta), a hydrophobic peptide with an ominous tendency to assemble into long-lived oligomers and polymers. Research by the PI has demonstrated that water-soluble Abeta extracted from AD brain can alter synaptic structure and function when applied to cultured neurons or injected into the brains of rodents. However, linking water-soluble Abeta and insoluble amyloid plaques (a pathological hallmark of AD) with the presence and severity of AD-type dementia is complicated by the fact that certain cognitively intact cases have appreciable amyloid pathology and relatively high levels of water-soluble Abeta. Although it is tempting to speculate that these individuals would in time develop AD, we simply do not know. Thus in this project we will acquire antemortem biomarker information to facilitate the study of 2 distinct categories of cognitively normal individuals: those with little risk of developing AD and those likely to develop AD. Similarly, we will also better characterize the amyloid deposits in the brain regions used for biochemical analysis. For instance, it has been reported that differences in plaque morphology are evident between demented cases and non-demented cases and that dementia can develop in the absence of significant plaque pathology.

In this project we will classify and document the types of amyloid deposits so as to understand if there is a link between the presence of certain types of amyloid deposits, water-soluble Abeta and the presence of AD-type dementia. Understanding this link should hasten the development of better disease biomarkers and facilitate the development of novel therapeutics designed to target water-soluble Abeta. As part of this effort the MD student will prepare and analyze homogenates from the brains of non-demented controls and individuals who died of AD. Analysis will involve the use of a variety of standard biochemical and immunological techniques including: ELISA, sedimentation analysis, size exclusion chromatography, immunoprecipitation and Western blotting. The student will have the opportunity to work as part of a team which will include a postdoctoral protein biochemist, a neuropathologist and the PI.