Abstract
Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer’s disease. Natural mutations in Aβ 42, such as the Arctic mutation (E22G) have been shown to increase Aβ 42 aggregation and neurotoxicity, leading to the early-onset of Alzheimer’s disease. A correlation between the propensity of Aβ 42 to form protofibrils and its effect on neuronal dysfunction and degeneration has been established. Using rational mutagenesis of the Aβ 42 peptide it was further revealed that the aggregation of different Aβ 42 mutants in lipid membranes results in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also have a variable ability to disrupt bilayer integrity. To further test the connection between Aβ 42 mutation and peptide–membrane interactions, we perform molecular dynamics simulations of membrane-inserted Aβ 42 variants (wild-type and E22G, D23G, E22G/D23G, K16M/K28M and K16M/E22G/D23G/K28M mutants) as β-sheet monomers and tetramers. The effects of charged residues on transmembrane Aβ 42 stability and membrane integrity are analyzed at atomistic level. We observe an increased stability for the E22G Aβ 42 peptide and a decreased stability for D23G compared to wild-type Aβ 42, while D23G has the largest membrane-disruptive effect. These results support the experimental observation that the altered toxicity arising from mutations in Aβ is not only a result of the altered aggregation propensity, but also originates from modified Aβ interactions with neuronal membranes.
Highlights
Alzheimer’s disease (AD) is the most common form of late-onset dementia resulting in the progressive impairment of memory and executive function [1]
The current study builds on our previous work, where we reported on the effects of lipid type and peptide oligomerization on membrane-bound WT Ab42 using molecular dynamics (MD) simulations on the sub-microsecond timescale [49]
The root mean square deviations (RMSD) and root mean square fluctuations (RMSF) are not sufficient to assess the structural change and stability of transmembrane peptides. Both E22G and K16M/K28M have average RMSD values of 0.40 nm, while the conformations shown in Fig. 2 reveal that the structures are different inside the membrane
Summary
Alzheimer’s disease (AD) is the most common form of late-onset dementia resulting in the progressive impairment of memory and executive function [1]. Ab is a normal product of cellular metabolism throughout life and circulates as a soluble peptide in biological fluids It is produced through posttranslational processing of the amyloid precursor protein (APP), a type-1 membrane integral glycoprotein via sequential cleavage by b- and c-secretases [4]. Of the proteolytic cleavage products, which typically contain 39 to 43 residues, Ab42 is recognized as the most important alloform based on its ability to elicit neurotoxicity. It is the most prevalent alloform found in amyloid plaques, and has the highest propensity to aggregate into fibrils and plaques [5,6]. A potential pathway for Ab toxicity lies in its ability to alter biophysical membrane properties [12,13,14], causing membrane disruption and permeability [15,16,17] and thereby allowing the leakage of ions, calcium ions [17,18,19,20]
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