Neurotoxic beta-amyloid peptide oligomers: biochemical isolation, conformational studies and neutralization in Alzheimer's Disease models

Abstract

The deposition of abnormal protein aggregates is associated with several neurodegenerative diseases. The most prevalent, Alzheimer's disease (AD), is characterized by the brain accumulation of aggregates formed by the Abeta peptide. Although the pathogenesis of AD is not fully understood, strong evidence indicate that soluble Abeta oligomers (AbOs) play a central role in the molecular basis of this dementia. The main objective of this project is to contribute to the understanding of the relationship between conformation and neurotoxicity of AbOs, with implications for the treatment of AD. For this, we will use as tool artificial scFv type antibodies with high selectivity for AbOs, named NUsc's, developed by our group. Using one of these, NUsc1, we have developed an assay for the biochemical isolation of a neurotoxic subpopulation of AbOs. We will apply this method to study the oligomeric state and the conformation of isolated AbOs, using biochemical and biophysical techniques. In parallel, we will study the neuroprotective potential of the combination of neutralizing AbOs using NUsc1 to the neuroprotection provided by the myokine irisin, using in vitro and in vivo models. Investigating new neuroprotective strategies against AbO toxicity is important to improve the cognitive benefit in patients treated with therapeutic antibodies directed against Abeta aggregates, such as the monoclonal IgG aducanumab, recently approved for clinical use by the FDA. By the end of this project, we hope to have determined the molecular mass (and therefore the oligomeric state) and conformational details of toxic AbOs, and to contribute to the development of more efficient therapeutic approaches against the cognitive loss in Alzheimer's disease patients. (AU)