Kerensa Broersen-Nutma
University of Twente, The Netherlands
Title: Prevention of protein misfolding in Alzheimer’s disease by an upgrade of the proteolytic enzyme machinery
Biography
Biography: Kerensa Broersen-Nutma
Abstract
One of the most prominent hallmarks detected in the brains of patients suffering from Alzheimer’s disease is the deposition of amyloidogenic plaques. These plaques are largely composed of the amyloid-beta peptide. It has been demonstrated that, even though these plaques comprise an important and recurring feature for disease, that precursor forms of these plaques, called ‘oligomers’ or ‘protofibrils’ more potently affect neuronal functioning. Accumulation and subsequent assembly of amyloid-beta peptide into aggregated forms has been reported to be partly brought about by an impaired clearance of the amyloid-beta peptide. Lowering the amyloid-beta peptide burden by increasing clearance provides a promising avenue for treatment of Alzheimer’s disease.
A number of proteases have been reported to cleave amyloid-beta peptide in vivo or in vitro. Drug compounds are under development that can modulate enzymatic activity to selectively enhance amyloid-beta peptide degradation. In view of the development of proteolytic-based therapies, more insight into the amyloid-beta peptide-degrading capacity of enzymes is required. For example, the effect of amyloid-beta proteolytic enzymes on various misfolded forms of the peptide has been little documented in the literature. Also the effect of in vivo occurring combinations of enzymes has not been explored. Moreover, the properties of enzyme-induced fragments from Aβ are currently unknown. To extend our understanding of the potential therapeutic utility of amyloid-beta peptide proteolytic enzymes, we investigated enzyme-mediated cleavage of amyloid-beta peptide in vitro using biophysical and biochemical assays and we identified new cleavage sites, cooperative activity of enzymes and characterized the potential aggregation behavior of resulting fragments.