It is well established that amyloid β-protein (Aβ) self-assembly is involved in triggering of Alzheimer's disease. On the other hand, evidence of physiological function of Aβ interacting with lipids has only begun to emerge. Details of Aβ–lipid interactions, which may underlie physiological and pathological activities of Aβ, are not well understood. Here, the effects of salt and 1,2-dimyristoyl- sn-glycero -3-phosphocholine (DMPC) lipids on conformational dynamics of Aβ42 monomer in water are examined by all-atom molecular dynamics (MD). We acquired six sets of 250 ns long MD trajectories for each of the three lipid concentrations (0, 27, and 109 mM) in the absence and presence of 150 mM salt. Ten replica trajectories per set are used to enhance sampling of Aβ42 conformational space. We show that salt facilitates long-range tertiary contacts in Aβ42, resulting in more compact Aβ42 conformations. By contrast, addition of lipids results in lipid-concentration dependent Aβ42 unfolding concomitant with enhanced stability of the turn in the A21–A30 region. At the high lipid concentration, salt enables the N-terminal region of Aβ42 to form long-range tertiary contacts and interact with lipids, which results in formation of a parallel β-strand. Aβ42 forms stable lipid–protein complexes whereby the protein is adhered to the lipid cluster rather than embedded into it. We propose that the inability of Aβ42 monomer to get embedded into the lipid cluster may be important for facilitating repair of leaks in the blood-brain barrier without penetrating and damaging cellular membranes.
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Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro
Naked mole-rats are extraordinarily long-lived rodents that offer unique opportunities to study the molecular origins of age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the ‘membrane pacemaker’ hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure.
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- Award ID(s):
- 1655494
- NSF-PAR ID:
- 10200659
- Date Published:
- Journal Name:
- Aging
- ISSN:
- 1945-4589
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.18632/aging.202138
