Polymorphic Aβ dimers are the smallest toxic species that play a role in the pathology of Alzheimer's disease. There is great interest in understanding the malfunctions that yield to these toxic species and in providing insights into the molecular mechanisms of the primary nucleation. Herein, we present a first work that demonstrates two distant edges states of Aβ dimers. The first is the so-called "random coil" state dimer that mimics the primary seeding/ nucleation that is far from a fibrillation state. The second is the "fibril-like" state dimer that is structurally in close proximity to the fibril, a well-organized state into a fibril-like structure. We show for the first time that a conformational change of one monomer within the dimer impedes primary nucleation, while less fluctuations and relatively large number of interactions in nucleation domains induce the primary nucleation to produce toxic stable species. Overall, the current study exhibits a diversity of primary nucleation in each dimer state, suggesting distinct molecular mechanisms of fibril formation. The conformations of the early stage Aβ dimers that were achieved may provide crucial data for designing inhibitors to impede the primary nucleation.

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Alzheimer's disease (AD) pathology is characterized by loss of memory cognitive and behavioral deterioration. One of the hallmarks of AD is amyloid β (Aβ) plaques in the brain that consists of Aβ oligomers and fibrils. It is accepted that oligomers, particularly dimers, are toxic species that are produced extracellularly and intracellularly in membranes. It is believed that the disruption of membranes by polymorphic Aβ oligomers is the key for the pathology of AD. This is a first study that investigate the effect of polymorphic “α‐helix/random coil” and “fibril‐like” Aβ dimers on 1,2‐dioleoyl‐ sn ‐glycero‐3‐phosphocholine (DOPC) membrane. It has been found that the DOPC membrane promotes Aβ 1–42 “fibril‐like” dimers and impedes Aβ 1–42 “α‐helix/random coil” dimers. The N‐termini domains within Aβ 1–42 dimers play a role in Aβ aggregation in membrane milieus. In addition, the aromatic π–π interactions (involving residues F19 and F20 in Aβ 1–42 ) are the driving forces for the hydrophobic interactions that initiate the primary nucleation of polymorphic Aβ 1–42 dimers within DOPC membrane. Finally, the DOPC bilayer membrane thickness is locally decreased, and it is disrupted by an embedded distinct Aβ 1–42 dimer, due to relatively large contacts between Aβ 1–42 monomers and the DOPC membrane. This study reveals insights into the molecular mechanisms by which polymorphic early‐stage Aβ 1–42 dimers have distinct impacts on DOPC membrane.

The difference between positive and negative studies was not explained by differences in the study population, the type of oil, or the duration of treatment. The significant difference apparently stems from the method of administration. When the oil was applied close to the olfactory system the outcome was positive. A study should be designed to assess the effect of the site of application of aromatherapy.

Clinical trials of past and current treatments for Alzheimer's disease (AD) patients on the market suffer from the dual drawbacks of a lack of efficacy and side effects. Neuropeptides have been highlighted by their potential to protect cells against AD and can reverse the toxic effect induced by Aβ in cultured neurons. One of the neuropeptides that has insufficient attention in the literature as a potential treatment for prevention of the progression of AD is neurokinin B (NKB). There are critical and unresolved questions concerning the activation, and the molecular mechanisms underlying NKB effect on prevention of Aβ aggregation remain unknown. The current work identifies for the first time the specific interactions that contribute to the inhibition and prevention of initial seeding of polymorphic earlystage dimers. Three main conclusions are observed in this work. First, NKB inhibits formation of polymorphic early-stage fibrillar Aβ dimers. The efficiency of the inhibition depends on the concentration of NKB (i.e., NKB:Aβ ratio). Second, NKB has an excellent effect of preventing the formation of initial seeding of early-stage nonfibrillar Aβ dimers. Third, NKB peptides may self-assemble to form cross-α fibril-like structure during the inhibition activity of the polymorphic early-stage fibrillar Aβ dimers but not during the prevention activity of early-stage nonfibrillar Aβ dimers. The work provides crucial information for future experimental studies to approve the functional effect of NKB on inhibition and prevention of Aβ polymorphic early-stage oligomers.