Strukturelle Grundlage biologisch aktiver Abeta-Konformere

01.03.2019 bis 28.02.2021

1 State of the art and preliminary work
Alzheimer’s disease (AD) and Aβ peptide
Alzheimer’s disease (AD) is one of the most prominent and socio-economically relevant neurodegenerative diseases. It is progressive and inevitably ends with death (Querfurth et al.,2010). AD cannot be cured and all available treatments are palliative or limited to a slightretardation of the cognitive decline (Gandy et al., 2013). AD is neuropathologically characterized by two types of protein aggregates (Fig. 1), one derived from Tau protein and the other consisting
of Aβ (or β-amyloid) peptide, a proteolytic fragment of the β-amyloid precursor protein (APP) (Haass et al. 2007; De Strooper et al., 2016). Strong evidence exists that Aβ peptide is closely linked to, if not the trigger of, AD pathophysiology. Genetic mutations in APP or in the proteins that are involved in the cleavage of Aβ from APP as well as chromosomal aberrations, which
increase the APP gene copy number per cell such as in Down’s syndrome, can lead to AD (Selkoe et al., 2016). Most of the available biomarker data imply Aβ to be crucial for the onset of disease (Musiek et al., 2014). A very large number of studies demonstrates that Aβ peptide is toxic to neuronal cells and alters the synaptic plasticity (Walsh et al, 2007), consistent with the observed
neuronal dysfunctions and cell loss in AD. Two main types of Aβ deposits can typically be found in AD patients: amyloid plaques within the brain parenchyma and vascular amyloid deposits, referred to as cerebral amyloid angiopathy (CAA). CAA amyloid consists primarily of the 40-residue peptide Aβ(1-40) (Glenner et al., 1984). Parenchymal amyloid consists primarily of the
42-residue peptide Aβ(1-42), (Masters et al., 1985). Besides these two ‘classical’ forms, several additional length variants and posttranslational modifications of Aβ peptide have been documented and most of which have been suggested to contribute to the disease process (Thal et al., 2015).
The strongest toxic activity is typically found with intermediate Aβ structures, such as oligomers or protofibrils that form transiently as the peptides self-assemble into mature amyloid fibrils (Lashuel et al., 2006; Walsh et al, 2007). Yet, these fibrils and their deposits are not necessarily non-pathogenic and benign. For example, the massive infiltrations of CAA amyloid make vessel walls brittle and cause hemorrhages and stroke in vivo (Thal et al., 2008). Aβ fibrils may also surface-catalyze the formation of toxic Aβ oligomers in vitro (Cohen et al., 2013) or undergo molecular recycling reactions (Sánchez et al., 2011) to release monomeric Aβ peptide, which may then become available to reassembly into more toxic structures. Consistent with these data, Aβ amyloid plaques were found to be surrounded by halos of soluble Aβ and altered neuronal activity (Spires-Jones et al., 2014). Finally, amyloid fibrillary structures play a crucial role in prion-like
transmission phenomena (see next section). In summary, intermediate Aβ aggregates represent likely the prime toxic forms of Aβ, yet Aβ fibrils also mediate pathological effects.