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Saccharide Modified Polyamines for the Prevention of Beta Amyloid Toxicity

James E. Henry, Cain Department of Chemical Engineering, Louisiana State University, 110 Chemical Engineering, South Stadium Rd, Baton Rouge, LA 70803

Alzheimer's disease (AD) is the leading cause of neurodegeneration in the United States, affecting approximately 4.5 million Americans in 2003, with an annual cost of care for these individuals estimated at over $100 billion. The cause of the neurotoxicity has been linked to the presence of Aβ fibrils. Aβ is a 39 to 43 amino acid long peptide that aggregates both in vivo and in vitro to form a variety of structures reported to be toxic and/or disease associated. These structures include a non-fibrillar species of approximately 17 to 42 kDa referred to as amyloid derived diffusible ligands (ADDLs), protofibrils species and fibril species. All the disease associated oligomers of Aβ have a high beta sheet content, in contrast to non-disease associated species. The currently most aggressively pursued Aβ oligomer target for both diagnostics and therapeutics is the ADDL.

In vivo, Aβ is known to accumulate in the cerebral cortex during disease, with deposition into mature amyloid plaques first in the entorhinal cortex and the hippocampus then later in the frontal cortex. During disease, it is apparent that Aβ accumulates in other parts of the body that are easier to sample for in vitro diagnostic measurements. Aβ circulates in both the blood and the cerebral spinal fluid. As disease progresses, there are significant changes in oligomeric Aβ in the cerebral spinal fluid.

While many investigators are developing structure specific antibodies for disease associated Aβ, there may be biomimetic materials that can be developed with antibody-like affinity but smaller molecular size that may be more appropriate for the demands of a neurotherapeutic. A variety of evidence indicates that Aβ may bind to cells via an interaction with surface sialic acids, and that the affinity of this interaction increases when the gangliosides or sialic acid molecules on the cell surface are clustered. Based on these data, it is hypothesized that biomimetic materials could be synthesized which would reproduce the clustered sialic acid structure of the cell surface, and therefore recreate the Aβ binding seen to occur on neuronal cell membranes.

It is proposed that targeting the fibrils will prevent toxicity by sequestering these fibrils. This technique has been demonstrated by previous work, but little has been done to improve the biomimicry of the sequestering agents. It is this area that will be explored. This technique relies on the attacking the theoretical “bottleneck” in the Alzheimer's process, the interaction of Aβ with neurons. This interaction is considered the bottleneck because there are several theorized environmental conditions that lead to the formation of Aβ fibrils. Additionally, the exact form of Aβ (3-mer, 5-mer, 12-mer, protofibril, fibril, etc) that interacts with the neuron is not concretely agreed upon. However, it is agreed that preventing neuronal interaction prevents toxicity.

A variety of evidence indicates that Aβ binds to cells via an interaction with surface glycolipids or glycoproteins with increased binding occurring in the presence of gangliosides or other clustered sialated molecules. Based on these data, it is hypothesized that membrane mimics could be synthesized which would reproduce the clustered sialic acid structure of the cell surface, and therefore compete with the cell surface for Aβ binding. While previous work has shown limited success, this work will greatly improve the knowledge toward intelligent molecule design and the efficacy of the sialated molecules. These results could have implications for the design of new agents that bind pathogenic Aβ peptides for the treatment of neurodegenerative disease. Based on our results, we will show the following results:

1. Production sialic acid modified polyamines.

2. Intrinsic toxicity of the new structures.

2. Efficacy of the molecules to prevent Aβ toxicity.