Location and Conformation of Amyloid β(25–35) Peptide and its Sequence‐Shuffled Peptides within Membranes: Implications for Aggregation and Toxicity in PC12 Cells

Abstract

Extracellular deposits of amyloid β (Aβ) aggregates in the brain is the hallmark of Alzheimer's disease. We present the configurations (location and conformation) and the interfacial folding and membrane insertion mechanisms of Aβ fragments, wild-type Aβ(25-35), Aβ(35-25), and a sequence-shuffled peptide [Aβ(25-35)-shuffled] from Aβ(25-35) within membranes by replica-exchange molecular dynamics simulations. Although these peptides have the same amino acid composition, simulations show they have distinct locations and conformations within membranes. Moreover, our in vitro experiments show that these peptides have distinct neurotoxicities. We rationalize the distinct neurotoxicities of these peptides in terms of their simulated locations and conformations in membranes. This work provides another view that complements the general hydrophobicity-toxicity views, to better explain the neurotoxicity of Aβ peptides.

Modelling of interactions between Aβ(25–35) peptide and phospholipid bilayers: effects of cholesterol and lipid saturation

“…Similar behaviour of Ab peptides was observed earlier in experimental work 26,29,32,39,40,107 and in simulations. 45,47,108 We can further note that observations made for Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) might be valuable for other amyloid peptides. For example, it was shown by Owen et al 109 and others 28,47 that insertion of the full Ab(1-42) peptide into the membrane can be hampered by membrane rigidity, that is, by a similar mechanism as observed for Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) in this work.…”

“…These ndings are coherent with conclusions from previous work where possible toxicity of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), as well as other Ab peptides is related to MET 35 and ASN 27 residues. 25,29,45,[111][112][113] Thus, Varadarajan et al 25 associated MET 35 with free radicals oxidative stress, by observing that the substitution of MET 35 by structurally similar norleucine removed the toxic effect. Friedemann et al 113 found that oxidation of MET 35 residues have a dumping effect on the aggregation of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

“…MET 35 appears to be the most pronounced promoter for binding between peptides and lipids in the bilayer as well as between peptides themselves. Perhaps, the reason for "activity" of this amino-acid in Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) is the fact that it is situated in the Cterminal and thus is able to bind by the carboxyl oxygen, as Tsai et al 45 showed that the reversed sequence has no toxic effects.…”

“…For Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide, a number of computational studies on the atomistic level regarding the structure of the peptide in different media have been carried out. 27,[41][42][43][44][45] Simulations of Ab peptides in the lipid bilayer environment are less common. We are aware of only about one work on the simulation of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) in a lipid bilayer environment which contains 11-palmitoyl-2-oleoyl-snglycero-3-phospho-(1 0 -rac-glycerol) (POPG) lipids.…”

Interaction of the β amyloid – Aβ(25–35) – peptide with zwitterionic and negatively charged vesicles with and without cholesterol

“…Frozza et al(Frozza et al, 2009) have presented strong evidence that Aβ(25–35) and Aβ(1–42) peptides induce similar neural injury, and thereby they recommended Aβ(25–35) as a convenient alternative for the investigation of neurotoxic mechanisms involved in AD. Also, several characteristics of Aβ(25–35) such as its amphiphilic nature, aggregation, neurotoxicity and ability to form β-sheet-rich fibrils are similar to those of the full-length Aβ peptide, ( Tsai et al, 2014; Smith and Klimov, 2018) and therefore Aβ(25–35) is a biologically active region of the full-length peptide (Smith and Klimov, 2018; Cuco et al, 2016). Ultimately, an understanding of how the Aβ(25–35) peptides change the fluidity and dielectric properties of the membrane may provide new insights on the mechanisms of the neurodegenerative process associated with AD.…”