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The ground-breaking research of patient H.M. brought to light the importance of the hippocampus for our memories of everyday and special events. Three quarters of a century of intense neurobiological and neuropsychological research would follow as scientists sought to understand why the hippocampus is such an important memory structure in the brain. Navigating a career during this time required adaptive research strategies as new evidence emerged. Although exciting progress has been made, complex challenges remain., (© 2024 Wiley Periodicals LLC.)

The underlying biophysical principle governing the cytotoxicity of the oligomeric aggregates of β‐amyloid (Aβ) peptides has long been an enigma. Here we show that the size of Aβ40 oligomers can be actively controlled by incubating the peptides in reverse micelles. Our approach allowed for the first time a detailed comparison of the structures and dynamics of two Aβ40 oligomers of different sizes, viz., 10 and 23 nm, by solid‐state NMR. From the chemical shift data, we infer that the conformation and/or the chemical environments of the residues from K16 to K28 are different between the 10‐nm and 23‐nm oligomers. We find that the 10‐nm oligomers are more cytotoxic, and the molecular motion of the sidechain of its charged residue K16 is more dynamic. Interestingly, the residue A21 exhibits unusually high structural rigidity. Our data raise an interesting possibility that the cytotoxicity of Aβ40 oligomers could also be correlated to the motional dynamics of the sidechains. [ABSTRACT FROM AUTHOR]

The accumulation of the amyloid‐β peptides (Aβ) is central to the development of Alzheimer's disease. The mechanism by which Aβ triggers a cascade of events that leads to dementia is a topic of intense investigation. Aβ self‐associates into a series of complex assemblies with different structural and biophysical properties. It is the interaction of these oligomeric, protofibril and fibrillar assemblies with lipid membranes, or with membrane receptors, that results in membrane permeability and loss of cellular homeostasis, a key event in Alzheimer's disease pathology. Aβ can have an array of impacts on lipid membranes, reports have included: a carpeting effect; a detergent effect; and Aβ ion‐channel pore formation. Recent advances imaging these interactions are providing a clearer picture of Aβ induced membrane disruption. Understanding the relationship between different Aβ structures and membrane permeability will inform therapeutics targeting Aβ cytotoxicity. [ABSTRACT FROM AUTHOR]

Extensive molecular dynamics simulations have been employed to probe the effects of salts on the kinetics and dynamics of early-stage aggregated structures of steric zipper peptides in water. The simulations reveal that the chemical identity and valency of cation in the salt play a crucial role in aggregate dynamics and morphology of the peptides. Sodium ions induce the most aggregated structures, but this is not replicated equivalently by potassium ions which are also monovalent. Divalent magnesium ions induce aggregation but to a lesser extent than that of sodium, and their interactions with the charged peptides are also significantly different. The aggregate morphology in the presence of monovalent sodium ions is a compact structure with interpenetrating peptides, which differs from the more loosely connected peptides in the presence of either potassium or magnesium ions. The different ways in which the cations effectively renormalize the charges of peptides are suggested to be the cause of the differential effects of different salts studied here. These simulations underscore the importance of understanding both the valency and nature of salts in biologically relevant aggregated structures. [ABSTRACT FROM AUTHOR]

A 22.5‐kg, 8.4‐year‐old female mixed breed dog was presented for an emergency ovariohysterectomy for pyometra. No neurological abnormalities were observed on preoperative physical examination. Surgery was completed uneventfully under fentanyl‐ and sevoflurane‐based anaesthesia. Cardiorespiratory indices remained stable under mechanical ventilation throughout the procedure. Approximately 23 min after the discontinuation of fentanyl infusion, the investigator noticed jaw closure and stiffness and thoraco‐abdominal muscle rigidity. To rule out fentanyl‐induced muscle rigidity, naloxone was administered. Following administration of naloxone, there was a return of spontaneous respiratory effort, indicated by capnogram and visible chest wall excursion. Based on the clinical signs and response to naloxone administration, the dog was diagnosed with suspected fentanyl‐induced muscle rigidity. Six minutes after the return of spontaneous respiration, the dog was extubated uneventfully without additional naloxone administration. During 4 days of postoperative hospitalization, no recurrent muscle rigidity was observed, and the patient was discharged safely. The total dose of fentanyl administered was 0.61 mg (27 μg kg−1). [ABSTRACT FROM AUTHOR]

Detecting novelty is critical to consolidate declarative memories, such as spatial contextual recognition memory. It has been shown that stored memories, when retrieved, are susceptible to modification, incorporating new information through an updating process. Catecholamine release in the hippocampal CA1 region consolidates an object location memory (OLM). This work hypothesized that spatial contextual memory updating could be changed by decreasing catecholamine release in the hippocampal CA1 terminals from the locus coeruleus (LC). In a mouse model expressing Cre-recombinase under the control of the tyrosine hydroxylase (TH) promoter, memory updating was impaired by photoinhibition of the CA1 catecholaminergic terminals from the LC (LC-CA1) but not from the ventral tegmental area (VTA-CA1). In vivo microdialysis confirmed that the extracellular concentration of both dopamine (DA) and noradrenaline (NA) decreased after photoinhibition of the LC-CA1 terminals (but not VTA-CA1) during the OLM update session. Furthermore, DA D1/D5 and beta-adrenergic receptor antagonists disrupted behavior, but only the former impaired memory updating. Finally, photoinhibition of LC-CA1 terminals suppressed long-term potentiation (LTP) induction in Schaffer's collaterals as a plausible mechanism for memory updating. These data will help understand the underpinning mechanisms of DA in spatial contextual memory updating. [ABSTRACT FROM AUTHOR]

The present study was aimed to develop silybin phytosome (SIBP) and evaluate its effectiveness against cerebral ischemia‐reperfusion (CIR) injury in rats. Initially, SIBP was prepared and characterized with Fourier transform‐infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Drug loading and entrapment efficiency of SIBP were also calculated. High‐performance liquid chromatography was used to carry out bioavailability studies of SIBP. Adult Wistar rats were divided randomly into five groups. The CIR injury was induced after 14 days of pretreatment by occlusion of bilateral common carotid arteries for 30 min followed by 4 h of reperfusion. Biochemical estimation, histopathological studies, and in silico studies were carried out. Bioavailability studies revealed that SIB concentration was increased to twofolds in SIBP‐treated rats. SIBP treatment significantly increases superoxide dismutase and glutathione levels while it decreases monoaldehyde, tumor necrosis factor‐α (TNF‐α), and interleukin 6 (IL‐6) levels in both the hippocampus and cortex of the SIBP‐treated CIR‐injured rats. Histopathological studies reveal SIBP treatment alleviates cortex cell death and arrangement of CA1 neurons in CIR‐injured rats. In silico studies against proteins (TNF‐α and IL‐6) involved in cerebral ischemia revealed that silybin (SIB) exhibits strong binding interaction with the target proteins when compared to thalidomide which was used as the positive control. Phytosome increase SIB bioavailability and SIBP treatment showed promising results when compared to treatment with SIB only. Based on our study, we conclude that phytosome is a suitable drug delivery agent to the brain for SIB as SIBP treatment was able to provide neuroprotective action against CIR injury. [ABSTRACT FROM AUTHOR]

By integrating a target-responsive MSN-based controlled release system with a sensitization-SPR co-enhanced thionine/MoS2 QDs/Cu NWs photocathode, a highly sensitive split-type PEC aptasensing platform for AβO detection in blood is constructed. Ultralow detection limit (2.1 fM) and high selectivity show great potential in early AD diagnosis. [ABSTRACT FROM AUTHOR]

The underlying biophysical principle governing the cytotoxicity of the oligomeric aggregates of β-amyloid (Aβ) peptides has long been an enigma. Here we show that the size of Aβ 40 oligomers can be actively controlled by incubating the peptides in reverse micelles. Our approach allowed for the first time a detailed comparison of the structures and dynamics of two Aβ 40 oligomers of different sizes, viz., 10 and 23 nm, by solid-state NMR. From the chemical shift data, we infer that the conformation and/or the chemical environments of the residues from K16 to K28 are different between the 10-nm and 23-nm oligomers. We find that the 10-nm oligomers are more cytotoxic, and the molecular motion of the sidechain of its charged residue K16 is more dynamic. Interestingly, the residue A21 exhibits unusually high structural rigidity. Our data raise an interesting possibility that the cytotoxicity of Aβ 40 oligomers could also be correlated to the motional dynamics of the sidechains., (© 2023 Wiley-VCH GmbH.)

A number of different proteins possess the ability to polymerize into filamentous structures. Certain classes of such assemblies can have key functional roles in the cell, such as providing the structural basis for the cytoskeleton in the case of actin and tubulin, while others are implicated in the development of many pathological conditions, including Alzheimer's and Parkinson's diseases. In general, the fragmentation of such structures changes the total number of filament ends, which act as growth sites, and hence is a key feature of the dynamics of filamentous growth phenomena. In this paper, we present an analytical study of the master equation of breakable filament assembly and derive closed-form expressions for the time evolution of the filament length distribution for both open and closed systems with infinite and finite monomer supply, respectively. We use this theoretical framework to analyse experimental data for length distributions of insulin amyloid fibrils and show that our theory allows insights into the microscopic mechanisms of biofilament assembly to be obtained beyond those available from the conventional analysis of filament mass only. [ABSTRACT FROM AUTHOR]

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation. [ABSTRACT FROM AUTHOR]

Although bis‐α‐amino acids have been used to synthesize dimer models of aggregative peptides involved in neurodegenerative diseases, tris‐α‐amino acids are employed to a lesser extent for trimer models. The reported tris‐α‐amino acids substituted on the 1,3,5‐positions of an aromatic ring are not suitable for mimicking trimers due to their low flexibility and high planarity. Here, we design and synthesize two new alkyl bridged‐tris‐α‐amino acids with Fmoc protecting groups as new flexible linkers for trimer models. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common of the multifactorial diseases and is characterized by a range of abnormal molecular processes, such as the accumulation of extracellular plaques containing the amyloid‐β (Aβ) peptides and dyshomeostasis of copper in the brain. In this study, we have investigated the effect of CuII on the aggregation of Aβ1–40 and Aβ4–40, representing the two most prevalent families of Aβ peptides, that is, the full length and N‐truncated peptides. Both families are similarly abundant in healthy and AD brains. For either of the studied peptides, substoichiometric CuII concentrations accelerated aggregation, whereas superstoichiometric CuII inhibited fibril formation, likely by stabilizing the oligomers. The addition of either Aβ4–40 or substoichiometric CuII affected the aggregation profile of Aβ1–40, by yielding shorter and thicker fibrils; amorphous aggregates were formed in the presence of a molar excess of CuII. The similarity of these two effects can be attributed to the increase in the positive charge on the Aβ N terminus, caused both by CuII complexation and N truncation at position 4. Our findings provide a better understanding of the biological Aβ aggregation process as these two Aβ species and CuII coexist and interact under physiological conditions. [ABSTRACT FROM AUTHOR]

Recent structural studies show distinct morphologies for the fibrils of Aβ(1–42) and Aβ(1–40), which are believed not to co-fibrillize. We describe here a novel, structurally-uniform 1 : 1 mixed fibrillar species, which differs from both pure fibrils. It forms preferentially even when Aβ(1–42) : Aβ(1–40) peptides are mixed in a non-stoichiometric ratio. [ABSTRACT FROM AUTHOR]

The biological function of proteins is dictated by the formation of supra-molecular complexes that act as the basic machinery of the cell. As such, measuring the properties of protein species in heterogeneous mixtures is of key importance for understanding the molecular basis of biological function. Here, we describe the combination of analytical microfluidic tools with liquid chromatography for multidimensional characterisation of biomolecules in complex mixtures in the solution phase. Following chromatographic separation, a small fraction of the flow-through is distributed to multiple microfluidic devices for analysis. The microfluidic device developed here allows the simultaneous determination of the hydrodynamic radius, electrophoretic mobility, effective molecular charge and isoelectric point of isolated protein species. We demonstrate the operation principle of this approach with a mixture of three unlabelled model proteins varying in size and charge. We further extend the analytical potential of the presented approach by analysing a mixture of interacting streptavidin with biotinylated BSA and fluorophores, which form a mixture of stable complexes with diverse biophysical properties and stoichiometries. The presented microfluidic device positioned in-line with liquid chromatography presents an advanced tool for characterising multidimensional physical properties of proteins in biological samples to further understand the assembly/disassembly mechanism of proteins and the nature of complex mixtures. [ABSTRACT FROM AUTHOR]

The amyloid cascade hypothesis attributes the neurodegeneration observed in Alzheimer's disease (AD) to the deposition of the amyloid β (Aβ) peptide into plaques and fibrils in the AD brain. The metal ion hypothesis which implicates several metal ions, viz. Zn2+, Cu2+ and Fe3+, in the AD pathology on account of their abnormal accumulation in the Aβ plaques along with an overall dyshomeostasis of these metals in the AD brain was proposed a while back. Metal ion chelators and ionophores, put forward as possible drug candidates for AD, are yet to succeed in clinical trials. Heme, which is widely distributed in the mammalian body as the prosthetic group of several important proteins and enzymes, has been thought to be associated with AD by virtue of its colocalization in the Aβ plaques along with the similarity of several heme deficiency symptoms with those of AD and most importantly, due to its ability to bind Aβ. This feature article illustrates the active site environment of heme-Aβ which resembles those of peroxidases. It also discusses the peroxidase activity of heme-Aβ, its ability to effect oxidative degradation of neurotransmitters like serotonin and also the identification of the highly reactive high-valent intermediate, compound I. The effect of second sphere residues on the formation and peroxidase activity of heme-Aβ along with the generation and decay of compound I is highlighted throughout the article. The reactivities of heme bound Aβ peptides give an alternative theory to understand the possible cause of this disease. [ABSTRACT FROM AUTHOR]

We report a method to fix the conformation of Aβ42 to the toxic or non-toxic form by intramolecular disulfide bonds. We found that an Aβ42 analog crosslinked within the molecule at the 17th and 28th amino acid residues exhibited high aggregative ability and potent neurotoxicity comparable to those of E22P-Aβ42. This analog would be useful in the research of Aβ42 oligomers and to develop reliable antibodies for early diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Stress and amyloid: The accumulation of β-amyloid (Aβ) plaques in the brain contributes to the symptoms of Alzheimer's disease (AD). Aβ is generated by the γ-secretase–mediated cleavage of amyloid precursor protein (APP), and γ-secretase activity is induced by cell stress, such as occurs with obesity and diabetes, which are major risk factors for AD. However, the use of γ-secretase inhibitors is limited by their disruption of other γ-secretase substrates. Using a gain-of-function screen in cells, diabetic AD model mice, and postmortem samples from patients with AD, Jung et al. identified the protein SERP1 as a cell stress–induced, APP-biased activator of γ-secretase. Knocking down SERP1 in cells or the mouse hippocampus decreased Aβ production, suggesting that blocking SERP1 might be a more selective therapeutic to reduce Aβ plaque formation in patients with AD. The enzyme γ-secretase generates β-amyloid (Aβ) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase–regulated substrates, such as Notch. Using a genome-wide functional screen of γ-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown γ-secretase activator that stimulates Aβ generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of γ-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the γ-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the γ-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing Aβ production. Moreover, SERP1 abundance, γ-secretase assembly, and Aβ production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, Aβ production was decreased by knocking down SERP1 in cells or in the hippocampi of mice. Compared to postmortem samples from control individuals, those from patients with AD showed increased SERP1 expression in the hippocampus and parietal lobe. Together, our findings suggest that SERP1 is an APP-biased regulator of γ-secretase function in the context of cell stress, providing a possible molecular explanation for the link between diabetes and sporadic AD. [ABSTRACT FROM AUTHOR]

We explore the long-time behavior and equilibrium properties of a system of linear filaments growing through nucleated polymerisation. We show that the length distribution for breakable filaments evolves through two well defined limiting cases: first, a steady state distribution determined by the balance of breakage and elongation is reached; upon monomer depletion at the end of the growth phase, an equilibrium length distribution biased towards smaller filament fragments emerges. We furthermore compute the time evolution of the concentration of small oligomeric filament fragments. For frangible filaments, oligomers are present both at early times and at equilibrium, whereas in the absence of fragmentation, oligomers are only present in significant quantities at the beginning of the polymerisation reaction. Finally, we discuss the significance of these results for the biological consequences of filamentous protein aggregation. [ABSTRACT FROM AUTHOR]

In this study, diffusion constants [translational (DT) and rotational (DR)], correlation times [rotational (τrot) and internal (τint)], and the intramolecular order parameters (S2) of the Alzheimer amyloid-β peptides Aβ40 and Aβ42 have been calculated from 150 ns molecular dynamics simulations in aqueous solution. The computed parameters have been compared with the experimentally measured values. The calculated DT of 1.61×10-6 cm2/s and 1.43×10-6 cm2/s for Aβ40 and Aβ42, respectively, at 300 K was found to follow the correct trend defined by the Debye–Stokes–Einstein relation that its value should decrease with the increase in the molecular weight. The estimated DR for Aβ40 and Aβ42 at 300 K are 0.085 and 0.071 ns-1, respectively. The rotational (Crot(t)) and internal (Cint(t)) correlation functions of Aβ40 and Aβ42 were observed to decay at nano- and picosecond time scales, respectively. The significantly different time decays of these functions validate the factorization of the total correlation function (Ctot(t)) of Aβ peptides into Crot(t) and Cint(t). At both short and long time scales, the Clore–Szabo model that was used as Cint(t) provided the best behavior of Ctot(t) for both Aβ40 and Aβ42. In addition, an effective rotational correlation time of Aβ40 is also computed at 18 °C and the computed value (2.30 ns) is in close agreement with the experimental value of 2.45 ns. The computed S2 parameters for the central hydrophobic core, the loop region, and C-terminal domains of Aβ40 and Aβ42 are in accord with the previous studies. [ABSTRACT FROM AUTHOR]

The assembly dynamics of two β sheets with different initial separation distances are explored by multiple all-atom molecular dynamics simulations with the presence of explicit water solvent. The β sheet is composed of seven identical peptides in an antiparallel fashion. The peptide sequence is the 20–29 segment of human Islet amyloid polypeptide. Our simulations show that the assembly occurs not only in the lateral direction but also along the longitudinal direction, which provides a new insight into the assembly pathway at the early stage of fibril elongation. Based on Poisson–Boltzmann free energy analysis and quasiharmonic configuration entropy estimation, the entropic contribution is found to play an important role in the longitudinal assembly. Moreover, a possible oligomeric state with cyclic form is suggested based on one assembly model found in the simulations, illustrating the polymorphic nature of aggregation of the amyloidogenic peptide. [ABSTRACT FROM AUTHOR]

Oligomers of Aβ peptides are suspected as the underlying cause of Alzheimer disease. Knowledge of their structural properties could therefore lead to a deeper understanding of the mechanism behind the outbreak of this disease. As a step in this direction we have studied Aβ dimers by all-atom molecular dynamics simulations. Equilibrated structures at 300 K were clustered into different families with similar structural features. The dominant cluster has parallel N-terminals and a well defined segment Leu17-Ala21 that are stabilized by salt bridges between Lys28 of one chain and either Glu22 or Asp23 of the other chain. The formation of these salt bridges may be the limiting step in oligomerization and fibrillogenesis. [ABSTRACT FROM AUTHOR]

The cytoxicity of Alzheimer’s disease has been linked to the self-assembly of the 40/42 amino acid of the amyloid-β (Aβ) peptide into oligomers. To understand the assembly process, it is important to characterize the very first steps of aggregation at an atomic level of detail. Here, we focus on the N-terminal fragment 1–28, known to form fibrils in vitro. Circular dichroism and NMR experiments indicate that the monomer of Aβ(1–28) is α-helical in a membranelike environment and random coil in aqueous solution. Using the activation-relaxation technique coupled with the OPEP coarse grained force field, we determine the structures of the monomer and of the dimer of Aβ(1–28). In agreement with experiments, we find that the monomer is predominantly random coil in character, but displays a non-negligible β-strand probability in the N-terminal region. Dimerization impacts the structure of each chain and leads to an ensemble of intertwined conformations with little β-strand content in the region Leu17-Ala21. All these structural characteristics are inconsistent with the amyloid fibril structure and indicate that the dimer has to undergo significant rearrangement en route to fibril formation. [ABSTRACT FROM AUTHOR]

There is experimental evidence suggesting that the toxicity of neurodegenerative diseases such as Alzheimer’s disease may result from the soluble intermediate oligomers. It is therefore important to characterize extensively the early steps of oligomer formation at atomic level. As these structures are metastable and short lived, experimental data are difficult to obtain and they must be complemented with numerical simulations. In this work, we use the activation-relaxation technique coupled with a coarse-grained energy model to study in detail the mechanisms of aggregation of four lys–phe–phe–glu (KFFE) peptides. This is the shortest peptide known to form amyloid fibrils in vitro. Our simulations indicate that four KFFE peptides adopt a variety of oligomeric states (tetramers, trimers, and dimers) with various orientations of the chains in rapid equilibrium. This conformational distribution is consistent with all-atom molecular-dynamics simulations in explicit solvent and is sequence dependent; as seen experimentally, the lys–pro–gly–glu (KPGE) peptides adopt disordered structures in solution. Our unbiased simulations also indicate that the assembly process is much more complex than previously thought and point to intermediate structures which likely are kinetic traps for longer chains. [ABSTRACT FROM AUTHOR]

We report the results of a study of the self-assembly of four minimalist peptide strands with a native β-barrel structure. Using a soft-well potential to mimic cellular crowding, molecular dynamics simulations were performed in confining spheres of varying radii. By utilizing a previously introduced scaling factor λ for the non-native hydrophobic interactions (0<λ<1), we were able to study models with varying degrees of frustration. Both the thermodynamics and kinetics of a Gō-like model (λ=0) and a highly frustrated model (λ=0.9) were studied. Additionally, we used an extrapolation technique to investigate the thermodynamics of assembly at intermediate values of λ. As in our earlier work [J. Chem. Phys. 118, 8106 (2003)] on a connected Gō-like model β-barrel protein, we find that the stability of the assembled protein increases with decreasing sphere size, and that larger confining spheres result in increased assembly times. Additionally, the λ=0 model seems to undergo distinct phase transitions during the assembly process. In contrast, the more frustrated model (λ=0.9) appears to undergo a glasslike transition at temperatures comparable to the assembly temperature of the Gō model, and that this transition is relatively nonspecific. Our results suggest the assembly process is dependent on both sequence and environment, with implications for the formation of misassembled aggregates. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The noradrenergic link: Norepinephrine (NE) and the noradrenergic system play a main role in cognition and noradrenergic changes have been documented in patients with Alzheimer's disease (AD). However, the role of NE in AD has not been completely elucidated. Here, Zhang et al. show that β-amyloid oligomers are allosteric ligands of the α2A adrenergic receptor (α2AAR) and modulate NE signaling, redirecting the pathway toward GSK3β activation and subsequent tau hyperphosphorylation. Blocking α2AAR reduced tau phosphorylation and ameliorated pathological and cognitive abnormalities in AD mouse models. The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50- to 100-fold lower than the amount required to activate GSK3β by Aβ alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD. [ABSTRACT FROM AUTHOR]

Based on the similar mechanism shared by diabetes mellitus (DM) and Alzheimer's disease (AD), we previously demonstrated that insulin-enhancing vanadyl complexes could preserve cognitive functions in an AD model of APP/PS1 mice after the emergence of β-amyloid (Aβ) plaques. Herein, we further studied the preventive effects of vanadyl complexes. Vanadyl acetylacetonate (VAC) was given to 3-month-old APP/PS1 mice, whose Aβ levels in the brain started to rise with unobservable deposits. Results showed that VAC could ameliorate Aβ pathogenesis in APP/PS1 mice but was less effective than that administrated at 5 months of age. Investigation on the molecular mechanism revealed that compared with vanadium treatment after Aβ plaque formation, earlier VAC administration showed increased clearance of Aβ deposition in the cerebral cortex, however, was much less effective in neuronal protection due to the failure to activate the Grp75 chaperone. These results suggest that neural cells under Aβ burden might exhibit different metabolic patterns and intracellular signal transduction before and after Aβ plaque formation, thus responding differently to vanadyl complexes at different intervention stages. Further studies clarifying the mechanism of the stage-dependent actions of vanadium would be helpful for the rational design of effective anti-AD vanadium agents and better understanding of AD pathogenesis. [ABSTRACT FROM AUTHOR]

The proteolytic resistant 33-mer gliadin peptide is an immunodominant fragment in gluten and responsible for the celiac disease and other gluten-related disorders. Meanwhile, the primary structure of the 33-mer is associated with the adaptive immune response in celiac patients, and the structural transformation of the 33-mer into protofilaments activates a primordial innate immune response in human macrophages. This means that accumulation, oligomerisation and structural transformation of the 33-mer could be the unknown first event that triggers the disease. Herein, we reveal the early stepwise mechanism of 33-mer oligomerisation by combining multiple computational simulations, tyrosine cross-linking, fluorescence spectroscopy and circular dichroism experiments. Our theoretical findings demonstrated that the partial charge distribution along the 33-mer molecule and the presence of glutamine that favours H-bonds between the oligomers are the driving forces that trigger oligomerisation. The high content of proline is critical for the formation of the flexible PPII secondary structure that led to a β structure transition upon oligomerisation. Experimentally, we stabilised the 33-mer small oligomers by dityrosine cross-linking, detecting from dimers to higher molecular weight oligomers, which confirmed our simulations. The relevance of 33-mer oligomers as a trigger of the disease as well as its inhibition may be a novel therapeutic strategy for the treatment of gluten-related disorders. [ABSTRACT FROM AUTHOR]

The multivariate analysis identified age at surgery (odds ratio (OR) 1.03), male (OR 2.8), prior resection (OR 2.9), diversion of stool (OR 4.3) and simultaneous colon resection (OR 2.5) to be associated with a higher risk of conversion to open surgery. The multivariate analysis identified lower pre-op albumin (odds ratio 0.89), males (OR 2), simultaneous colonic (OR 7.3) resection and prior resection (OR 2.8 per previous surgery) to be significantly associated with stoma formation. 25 patients (52%) were managed by flatus tube, 13 patients (27%) were successfully decompressed with flexible sigmoidoscopy, however, 10 patients (21%) required urgent Hartman's procedure. 4 patients were fit and underwent elective surgery, 8 patients were deemed unfit by anaesthetists, 2 declined surgery. Completeness of the bowel preparation of 78 patients was good in 52 patients and poor in 26 patients (33.3%). [Extracted from the article]

Alzheimer's disease is associated with the abnormal self-assembly of amyloid-β (Aβ) peptide into toxic oligomers and fibrils. Recent experiments reported that Aβ16−22, containing the central hydrophobic core (CHC) of Aβ, formed antiparallel β-sheet fibrils, while its E22Q mutant self-assembled into parallel β-sheet fibrils. However, the molecular mechanisms underlying E22Q-mutation-induced parallel β-sheet fibril formation are not well understood. Herein, we performed molecular dynamics (MD) simulations to study the dimerization processes of Aβ16−22 and Aβ16−22E22Q peptides. β-Sheet dimers with diverse hydrogen bond arrangements were observed and they exhibited highly dynamic and interconverting properties. An antiparallel-to-parallel β-sheet transition occurred in the assembly process of the E22Q mutant, but not in that of Aβ16−22. During this conformational transformation process, the inter-molecular Q22–Q22 hydrogen bonds were first formed and acted as a binder to facilitate the two chains forming a parallel orientation, then the hydrophobic interactions between residues in the CHC region consolidated this arrangement and drove the main-chain H-bond formation, hence resulting in parallel β-sheet formation. However, parallel β-sheets were less populated than antiparallel β-sheets of Aβ16−22E22Q dimers. In order to explore whether parallel β-sheets became dominant in larger size oligomers, we investigated the conformational ensembles of Aβ16−22 and Aβ16−22E22Q octamers by conducting replica exchange molecular dynamics (REMD) simulations. The REMD simulations revealed that the population of parallel β-strand alignment increased with an increase of the size of ordered Aβ16−22E22Q β-sheet oligomers, implying that the formation of full parallel β-sheets requires larger sized oligomers. Our findings provide a mechanistic explanation for the E22Q-mutation-induced formation of parallel β-sheet fibrils observed experimentally. [ABSTRACT FROM AUTHOR]