As the intrinsic origin of the hypothesis for β-amyloid (Aβ) from Alzheimer’s disease, histidine behaviors were found to play a crucial role in Aβ aggregation. To investigate the histidine behaviors during the early stage of aggregation, Aβ40/42 pentamers with different histidine isomer states were simulated at the atomic level. Results show that five Aβ40 (δδδ) and Aβ42 (εδδ) monomers can rapidly decrease the aggregation threshold, promote stable pentamer formation, and increase pentamer contents by 51.8% and 56.7%, respectively, as compared with the values of their wild-type (εεε) counterparts. Additionally, pentamers of Aβ40 (δδδ) and Aβ42 (εδδ) have different aggregation pathways and disassembly species, Tr+D and Te+M, during the growth of the pentamer. This work discloses the significance of histidine tautomerization in Aβ aggregation, implying a potential way to control Aβ aggregation and develop the assembly inhibitors.

Alzheimer's disease (AD) is characterized by fibrillar deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles of Tau proteins. Aβ peptides are composed of 37−49 residues, among which the Aβ 42 isoform is particularly toxic and aggregation-prone and is enriched in the plaques of AD brains and thus considered central to the development of AD. Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aβ aggregation. Here we capture the atomic-level details of the interactions between sigmoid Aβ 42 fibril 2MXU or 5KK3 and either natural tanshinone compounds TS1 or TS0 or negatively charged ER, proposing two unprecedented disassembly mechanisms. Natural TS1 or TS0 prefers to insert into the cavity together with part at the surface of the 2MXU to open up the mouth and twist the conformation, destroying the ordered growth of subsequent monomers along the fibril axis. For the more compact two-fold 5KK3, attachment of TS1 or TS0 at the surface including some inserted in cavity results in the separation of the two folds. In the two sigmoid fibril systems, it is no longer applicable for the routine criteria to assess Aβ 42 fibril disassembly by introduction of these drugs, such as either reduced H-bond number, decreased β-sheet contents, or both. ER, like-charged to Aβ 42 fibril, is especially exceptional, and departs utterly from the neutral ones to disassemble Aβ 42 fibril. Besides the inapplicable routine criteria, positive binding energy between ER and Aβ 42 fibril also deviates from the hypotheses of "ligands exhibiting greater affinity for the β-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity" (Cairo et al.et al., Biochemistry 2002, 41, 8620−8629) but results in stronger disassembly effect on the two kinds of sigmoid Aβ 42 fibrils than neutral TS0 or TS1. The disassembly power of charged ER molecules derives from its stronger deformation ability to the conformation of Aβ 42 fibril than the neutral ones, twisting the one-fold 2MXU into tapered-shape and separating two-fold 5KK3 in two parts further, which is in great agreement with experimental observations (Irwin et al.et al. Biomacromolecules 2013, 14 (1), 264−274). The unusual disassembly mechanisms fill the gaps and offer an alternative direction in engineering new inhibitors to treat AD.

Toll-like receptor 4 (TLR4) has been linked to various pathophysiological conditions, such as traumatic brain injury (TBI). It is reported that posttraumatic neuroinflammation is an essential event in the progression of brain injury after TBI. Recent evidences indicate that TLR4 mediates glial phagocytic activity and inflammatory cytokines production. Thus, TLR4 may be an important therapeutic target for neuroinflammatory injury post-TBI. This study was designed to explore potential effects and underlying mechanisms of TLR4 in rats suffered from TBI. TBI model was induced using a controlled cortical impact in rats, and application of TLR4 shRNA silenced TLR4 expression in brain prior to TBI induction. Elevated TLR4 was specifically observed in the hippocampal astrocytes and neurons posttrauma. Interestingly, TLR4 shRNA decreased the concentrations of interleukin (IL)-1β, IL-6, and tissue necrosis factor-α; alleviated hippocampal neuronal damage; reduced brain edema formation; and improved neurological deficits after TBI. Meanwhile, to further explore underlying molecular mechanisms of this neuroprotective effects of TLR4 knockdown, our results showed that TLR4 knockdown significantly inhibited the upregulation of autophagy-associated proteins caused by TBI. More importantly, an autophagy inducer, rapamycin pretreated, could partially abolish neuroprotective effects of TLR4 knockdown on TBI rats. Furthermore, TLR4 silencing markedly suppressed GFAP upregulation and improved cell hypertrophy to attenuate TBI-induced astrocyte activation. Taken together, these findings suggested that TLR4 knockdown ameliorated neuroinflammatory response and brain injury after TBI through suppressing autophagy induction and astrocyte activation.

Amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer’s disease. Unraveling the seeding region and related context as well as their association can help in having an insight into...

Aggregation of amyloid beta (Aβ) is a central step of Alzheimer's disease. Aβ42 monomers are building blocks in the formation of both “on pathway” intermediate structures and “off pathway” oligomers. How to sample an Aβ monomer becomes a problem however due to the instinct of Aβ high flexibility and diversity as well as aggregation propensity. Currently, (1) most samplings focus on either the ready‐made helix‐rich 1Z0Q/1IYT NMR structure, or the completely extended conformation, but (2) few on a ready‐made Aβ NMR fibril (i. e., 2BEG). Here we compare the simulation results from sampling in scheme (1) with that in scheme (2), and find that the coil and β‐sheet contents in the 1Z0Q‐sampled system are comparable to the counterparts in the 2BEG‐sampled system, but with a large difference in simulation time and dynamics character. 1Z0Q‐sampled system not only takes several times longer than the 2BEG‐sampled one, and only β1‐seeding dynamics characteristic is observed probably due to far insufficient conformation transition in the limited simulation time. Two dynamics characteristics of Aβ42 folding observed experimentally, that either β1 region or β2 region aggregates first, reproduce in the present simulations for 2BEG‐sampled system however, suggesting a preferential sampling in the future simulation. In addition, a turn‐β‐strand synergetic seeding mechanism of aggregation is first proposed based on the trajectory analyses on the four regions of Aβ42 chain.