Structural insight into the interaction of amyloid-β peptide with biological membranes by solid state NMR

Abstract

Alzheimer’s disease (AD) is a chronic dementia, affecting an increasingly large number of old people worldwide [1–3]. AD together with mature onset diabetes and prion-transmissible spongiform encephalopathies, belongs to a category of amyloid diseases, which are all categorized by an abnormal folding of a normally soluble protein into neurotoxic aggregated structures [3–5]. The key event in AD is the metabolism of amyloid precursor protein to amyloid-β-peptide (Aβ) and the subsequent deposition of Aβ as plaques in the brains of patients. This 39–42 amino acid peptide has been linked to the apoptosis of neuronal cells, and its neurotoxicity seems to be associated with its ability to convert from a non-toxic monomeric form into toxic aggregates [5–7]. However the cellular mechanism involved in mediating the toxic effect of Aβ peptide remains unclear [6–11]; and also the process of transformation into insoluble, neurotoxic peptide aggregates. Due to the complexity and dependence of this process on physiological parameters, various models for fibril formation are studied at present including aggregation in solution [7,8], lipid-mediated aggregation of Aβ in contact with cell membrane surfaces [10–13], and formation of transmembrane ion channel-like structures in neuronal membranes [9,14,15]. Structural and biophysical studies of the self-assembly of Aβ-peptide into fibrillar structures found this process strongly dependent on the physical conditions [5,6–8,16]. While earlier studies proposed antiparallel-β-sheet structures for the amyloid fibrils [6], more recent work indicates an in register, parallel organization of β-sheets propagating and twisting along the fibrillar axis [5,17]. However, there is growing evidence that the toxic agent is not the mature fibrils themselves, but rather their precursor forms called diffusible “protofibrils” [3,4,8].