Comparison of computed data from the model and experimental data from Cramer et al. and Veeraghavalu et al.

<p>Computed data of six-month-old <i>APP</i>/<i>PS1</i> mice treated with 100 mg ⋅ kg⁻¹ of bexarotene for seven days is compared to the experimental results of Cramer et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.ref001" target="_blank">1</a>] and the results presented in Fig 1 of Veeraghavalu et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.ref007" target="_blank">7</a>].</p

Comparison of computed data from the model and experimental data from Cramer et al.

<p>(A) Computed data from the model is compared to that from Fig 2 of Cramer et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.ref001" target="_blank">1</a>], <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.s007" target="_blank">S4</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.s008" target="_blank">S5</a> Figs of the supporting online materials to Cramer et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.ref001" target="_blank">1</a>] of <i>APP</i>/<i>PS1</i> mice at six-months-old given treatment for three, seven and 14 days; nine-months-old given treatment for 90 days; and at 11-months-old given seven days of treatment. All treatment is for 100 mg ⋅ kg⁻¹ bexarotene.</p

Initial values and parameters used for simulation plots. The value for <i>A</i>(0) was obtained from Fig 3 of Trinchese and Liu [11]. The value of <i>r</i> was calculated using bexarotene half-life data from Fig 1 of Landreth and Cramer [6].

<p>Initial values and parameters used for simulation plots. The value for <i>A</i>(0) was obtained from Fig 3 of Trinchese and Liu [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.ref011" target="_blank">11</a>]. The value of <i>r</i> was calculated using bexarotene half-life data from Fig 1 of Landreth and Cramer [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153150#pone.0153150.ref006" target="_blank">6</a>].</p

Reaction scheme of Aβ production and treatment.

<p>Reaction scheme of Aβ production and treatment.</p

Correction: Early Treatment Critical: Bexarotene Reduces Amyloid-Beta Burden In Silico

<p>Correction: Early Treatment Critical: Bexarotene Reduces Amyloid-Beta Burden In Silico</p

Early Treatment Critical: Bexarotene Reduces Amyloid-Beta Burden In Silico

<div><p>Amyloid-beta peptides have long been implicated in the pathology of Alzheimer’s disease. Bexarotene, a drug approved by the U.S. Food and Drug Administration for treating a class of non-Hodgkin’s lymphoma, has been reported to facilitate the removal of amyloid-beta. We have developed a mathematical model to explore the efficacy of bexarotene treatment in reducing amyloid-beta load, and simulate amyloid-beta production throughout the lifespan of diseased mice. Both aspects of the model are based on and consistent with previous experimental results. Beyond what is known empirically, our model shows that low dosages of bexarotene are unable to reverse symptoms in diseased mice, but dosages at and above an age-dependent critical concentration can recover healthy brain cells. Further, early treatment was shown to have significantly improved efficacy versus treatment in older mice. Relevance with respect to bexarotene-based amyloid-beta-clearance mechanism and direct treatment for Alzheimer’s disease is emphasized.</p></div

Simulation of healthy brain cell concentration for six month-old <i>APP</i> / <i>PS1</i> mouse with varying bexarotene dosage and frequency of treatment.

<p>Treatment is varied from constant, daily, alternate-day, and weekly addition of bexarotene. Bexarotene is given in dosages from 0 mg ⋅ kg⁻¹ to 1000 mg ⋅ kg⁻¹ of a period of two weeks.</p

Index of rate constant and parameter definitions.

<p>Index of rate constant and parameter definitions.</p

Alzheimer’s Protective Cross-Interaction between Wild-Type and A2T Variants Alters Aβ₄₂ Dimer Structure

Whole genome sequencing has recently revealed the protective effect of a single A2T mutation in heterozygous carriers against Alzheimer’s disease (AD) and age-related cognitive decline. The impact of the protective cross-interaction between the wild-type (WT) and A2T variants on the dimer structure is therefore of high interest, as the Aβ dimers are the smallest known neurotoxic species. Toward this goal, extensive atomistic replica exchange molecular dynamics simulations of the solvated WT homo- and A2T hetero- Aβ_1–42 dimers have been performed, resulting into a total of 51 μs of sampling for each system. Weakening of a set of transient, intrachain contacts formed between the central and C-terminal hydrophobic residues is observed in the heterodimeric system. The majority of the heterodimers with reduced interaction between central and C-terminal regions lack any significant secondary structure and display a weak interchain interface. Interestingly, the A2T N-terminus, particularly residue F4, is frequently engaged in tertiary and quaternary interactions with central and C-terminal hydrophobic residues in those distinct structures, leading to hydrophobic burial. This atypical involvement of the N-terminus within A2T heterodimer revealed in our simulations implies possible interference on Aβ₄₂ aggregation and toxic oligomer formation, which is consistent with experiments. In conclusion, the present study provides detailed structural insights onto A2T Aβ₄₂ heterodimer, which might provide molecular insights onto the AD protective effect of the A2T mutation in the heterozygous state

Weaker N‑Terminal Interactions for the Protective over the Causative Aβ Peptide Dimer Mutants

Knowing that abeta amyloid peptide (Aβ₄₂) dimers are the smallest and most abundant neurotoxic oligomers for Alzheimer’s disease (AD), we used molecular simulations with advanced sampling methods (replica-exchange) to characterize and compare interactions between the N-termini (residues 1–16) of wild type (WT-WT) and five mutant dimers under constrained and unconstrained conditions. The number of contacts and distances between the N-termini, and contact maps of their conformational landscape illustrate substantial differences for a single residue change. The N-terminal contacts are significantly diminished for the dimers containing the monomers that protect against (WT-A2T) as compared with those that predispose toward (A2V-A2V) AD and for the control WT-WT dimers. The reduced number of N-terminal contacts not only occurs at or near the second residue mutations but also is distributed through to the 10th residue. These findings provide added support to the accumulating evidence for the “N-terminal hypothesis of AD” and offer an alternate mechanism for the cause of protection from the A2T mutant