Influence of genetic variability and external regulating factors on amyloid-beta peptide aggregation

Protein aggregation has been associated with a wide range of highly debilitating and increasingly prevalent human diseases, ranging from neurodegenerative disorders to non-neuropathic amyloidoises. One of the most widespread neurodegenerative diseases is Alzheimer’s disease (AD), which is the leading cause of dementia, affecting millions of people worldwide and imposing an enormous economic burden in terms of health and hospice care. Substantial evidence points to the amyloid-beta (Aβ) peptide as a major causative factor in AD. This apparently harmless intrinsically disordered monomeric peptide converts into higher ordered and toxic aggregates, and eventually into amyloid fibrils that deposit into extracellular plaques in the brain. One of the leading hypothesis states that Aβ aggregation initiates a cascade of molecular events culminating in widespread neurodegeneration. Several drug discovery strategies have therefore been directed at interfering with Aβ production, aggregation, clearance or toxicity. However, clinical trials have been unsuccessful up to date due to a lack of efficacy or safety issues. This lack of success reflects the general failure to fully comprehend amyloid deposition and its dynamics. The research presented in this doctoral thesis aims to provide more insight into Aβ dynamics and its implication for AD therapy. First, the dynamic nature of Aβ is illustrated and is defined at the intra- and intermolecular level. Next, the influence of genetic variability and external regulating factors on Aβ dynamics, in particular on the aggregation and structural properties of Aβ, was investigated in vitro using a biophysical approach complemented with cell culture studies. Genetic variability includes different Aβ peptide lengths and mutants, originating from mutations within genes encoding amyloid precursor protein and secretases, and Apolipoprotein E (ApoE), the major lipid transporter in the brain of which the ApoE4 isoform is a major genetic risk factor for AD. External regulating factors that were investigated comprise insulin-degrading enzyme, a well-known Aβ-degrading enzyme, and peptidomimetics capable of interfering with Aβ aggregation. Both single- and potential multi-target AD treatment strategies are considered, and I suggest that combining network medicine with general ecosystem management principles is a new holistic approach to better understand AD mechanisms and potentially design more successful therapies.