Understanding the mechanism of and preventing beta-amyloid induced neurotoxicity in Alzheimer's disease

The Alzheimer's Association estimated this year that every 72 seconds, someone in America develops Alzheimer's Disease (AD). This devastating and fatal disease is the leading cause of neurodegeneration and costs the country almost a {dollar}150 billion annually. AD brains are marked with the deposition of extracellular plaques, the primary component of which is a 39-43 amino acid peptide called beta-amyloid (Abeta). Abeta is implicated as the neurotoxic disease causing entity and its neurotoxicity is a function of its aggregated state. Abeta monomer is thought to aggregate to spheroidal oligomers, protofibrils and fibrils that are toxic to neurons to different degrees. It is now the general consensus that intermediate species such as oligomers and protofibrils are more toxic than the fibril end products of Abeta aggregation. Yet, we still do not have a clear identification of the most toxic of Abeta structural species. Properties that attribute to Abeta neurotoxicity require clarity in understanding.; One of the difficulties the scientific community has faced in studying properties of toxic Abeta aggregates is the lack of in vitro toxicity assays able to measure Abeta toxicity before the peptide undergos considerable structure change. Assays that have routinely been used to measure Abeta toxicity required on average 24 h protein incubation with cells. Abeta structural change occurs on a time scale of hours. An in vitro toxicity assay that required only 2 h protein incubation with cells was developed enabling us to measure toxicity of intermediate transient Abeta structural species.; Using hydrogen-deuterium exchange mass spectroscopy along with this fast toxicity assay, the solvent accessibility properties of aggregated Abeta were correlated with their potential for neurotoxicity. It was found that the most toxic intermediate species showed much more protection from solvent than the monomer and less than that of fibrils. The toxicity of Abeta samples correlated with the abundance of these intermediate species in the samples.; Abeta induced GTP binding protein (G protein) activation has been found to be a step towards neurotoxic destruction of cells. Understanding the variables affecting this interaction in more detail can help us find therapeutic targets for the disease. A mechanistic model of Abeta induced G protein activation was developed to explain the role of cholesterol and gangliosides on the cell surface in such interactions. It was found that both molecules play an active part in Abeta induced G protein activation, and that Abeta binding to gangliosides in particular was essential for the G protein activation observed to correlate with neurotoxicity.; Drugs available for AD today provide only symptomatic relief from the disease. Thus far, there are no FDA approved disease-modifying agents. From studies in animal models and clinical trials of Abeta immunization, it is known that removing Abeta or sequestering the peptide away from neurons not only inhibit further Abeta induced cellular damage but it can also reverse previous damage caused by Abeta. Abeta preferentially binds to cell membrane clustered sialic acid containing gangliosides. Mimic molecules of clustered sialic acid that compete with cell surface sialic acid for Abeta binding have been developed. These molecules have shown to mitigate Abeta induced neurotoxicity in vitro, probably by sequestering the peptide away from neurons, and show promise as therapeutics for AD.