Generation of Aβ peptides and characterization of their molecular
interactions in the formation of toxic oligomers

SUMMARY

The amyloid-β precursor protein (APP) is first cleaved by the β-site APP cleaving enzyme (BACE) and then subsequentially processed by the γ- secretase complex to generate amyloid-β (Aβ) peptides of varying length. Aβ peptides represent the main culprits in the pathogenesis of Alzheimer disease (AD). Earliest aggregates easily self assemble into fibrils and are deposited in plaques.

There is increasing evidence that soluble low-n Aβ42 oligomers play a crucial role early in the pathogenesis of AD, as they were described to be neurotoxic and to cause cognitive deficits long before amyloid plaques are detectable. However, the exact toxic mechanism remains unclear.

In this project two different aspects will be analyzed. The sequential cleavage mechanism of the γ-secretase which leads to the generation of Aβ42 peptides will be elucidated on the molecular level. The aims are to investigate how toxic Aβ oligomers are generated during and/or after the processing of APP by the γ-secretase and how the peptides of different length are released from the γ-secretase complex.

In addition, the hydrophobic interactions of the resulting Aβ-peptides which leads to the aggregation of Aß peptides into oligomers and the association of these oligomers with lipids and/or potential membrane-bound receptors will be analyzed. The biochemical analysis of Aβ-Aβ or Aβ-lipid interactions will provide new insight into the mechanisms how these peptides mediate the toxicity on the molecular level.

The identification of the molecular interactions of toxic oligomers will open up a new avenue to identify and to combat disease causes in AD.