Amyloid-β Peptide Research Articles

Investigating the Impact of Intracerebroventricular Streptozotocin on Female Rats with and without Ovaries: Implications for Alzheimer's Disease.

To contribute to research on female models of Alzheimer's disease (AD), our aim was to study the effect of intracerebroventricular (ICV) injection of streptozotocin (STZ) in female rats, and to evaluate a potential neuroprotective action of ovarian steroids against STZ. Female rats were either ovariectomized (OVX) or kept with ovaries (Sham) two weeks before ICV injections. Animals were injected with either vehicle (artificial cerebrospinal fluid, aCSF) or STZ (3mg/kg) and separated into four experimental groups: Sham + aCSF, Sham + STZ, OVX + aCSF and OVX + STZ. Nineteen days post-injection, we assessed different behavioral aspects: burying, anxiety and exploration, object recognition memory, spatial memory, and depressive-like behavior. Immunohistochemistry and Immunoblot analyses were performed in the hippocampus to examine changes in AD-related proteins and neuronal and microglial populations. STZ affected burying and exploratory behavior depending on ovarian status, and impaired recognition but not spatial memory. STZ and ovariectomy increased depressive-like behavior. Interestingly, STZ did not alter the expression of β-amyloid peptide or Tau phosphorylated forms. STZ affected the neuronal population from the Dentate Gyrus, where immature neurons were more vulnerable to STZ in OVX rats. Regarding microglia, STZ increased reactive cells, and the OVX + STZ group showed an increase in the total cell number. In sum, STZ partially affected female rats, compared to what was previously reported for males. Although AD is more frequent in women, reports about the effect of ICV-STZ in female rats are scarce. Our work highlights the need to deepen into the effects of STZ in the female brain and study possible sex differences.

Amyloid-β peptide treatment reverses bone loss in the mandibular condyle via Wnt signalling pathway

ObjectiveTo explore the effect of amyloid-β peptide (Aβ) on mandibular condyle to develop a new treatment for postmenopausal women with Temporomandibular joint osteoarthritis. MethodsA murine bone loss model was established by ovariectomy. Microstructure parameters of the condyle were measured by microcomputed tomography before and after intraperitoneal injection with Aβ. Flow cytometry, Alizarin red staining, RT-qPCR assays, FITC/PI staining, Oil Red O staining and western blotting were used to evaluate the effect of Aβ on the osteogenic differentiation of mouse bone marrow stromal stem cells (mBMSCs). ResultsIn vivo, condylar microstructure parameters increased. Serum osteoprotegerin and procollagen type 1 N propeptide increased in a dose-dependent manner after the injection of Aβ, which were opposite the changes observed in c-terminal telopeptides of type I collagen, tumor necrosis factor-α and the high serum level of leptin. In vitro, Aβ promoted calcium nodule formation in the cells. The expression of ALP, Runx2, osteorix and osteocalcin increased significantly. The expression of mRNAs related to the Wnt signaling pathway was significantly upregulated, which could be blocked by DKK1. ConclusionAβ can reverse bone loss in the mandibular condyle in ovariectomized mice through promoting the osteogenic differentiation of mBMSCs via the Wnt pathway.

A Snake Venom Peptide and Its Derivatives Prevent Aβ42 Aggregation and Eliminate Toxic Aβ42 Aggregates In Vitro.

Over a century has passed since Alois Alzheimer first described Alzheimer's disease (AD), and since then, researchers have made significant strides in understanding its pathology. One key feature of AD is the presence of amyloid-β (Aβ) peptides, which form amyloid plaques, and therefore, it is a primary target for treatment studies. Naturally occurring peptides have garnered attention for their potential pharmacological benefits, particularly in the central nervous system. In this study, nine peptide derivatives of Crotamine, a polypeptide from Crotalus durissus terrificus Rattlesnake venom, as well as one d-enantiomer, were evaluated for their ability to modulate Aβ42 aggregation through various assays such as ThT, QIAD, SPR, and sFIDA. All tested peptides were able to decrease Aβ42 aggregation and eliminate Aβ42 aggregates. Additionally, all of the peptides showed an affinity for Aβ42. This study is the first to describe the potential of crotamine derivative peptides against Aβ42 aggregation and to identify a promising d-peptide that could be used as an effective pharmacological tool against AD in the future.

DNA Nanocage-Assisted Size-Selective Recognition and Quantification toward Low-Mass Soluble β-Amyloid Oligomers.

Low-mass soluble β-amyloid peptide oligomers (LSAβOs) play a crucial role in the pathogenesis of Alzheimer's disease. However, these oligomers exhibit heterogeneity in terms of structure, stability, and stoichiometry, and their abundance in biofluids is low, making accurate identification challenging. In this study, we developed a DNA nanocage-assisted method for selective sizing and sensitive quantification of LSAβOs in serum. Using LSAβO less than 10 kDa (LSAβO10kD) and less than 30 kDa (LSAβO30kD) as models, the size-matching rules between DNA nanocages and LSAβOs were investigated, and two appropriate nanocages were selected for the detection of two LSAβOs, respectively. Both nanocages were functionalized by encapsulating oligomer's aptamer and a complementary sequence within their cavities. Once the LSAβO entered the corresponding nanocage cavity, the complementary sequence was released, triggering a hybridization chain reaction on an electrochemical sensing platform. The system achieved size-selective discrimination of LSAβO10kD with a linear range of 10-150 pM and LSAβO30kD with a linear range of 15-150 pM. Real sample testing confirmed the applicability of the method for blood-based diagnosis. The DNA nanocage-assisted electrochemical analysis platform provides an accurate, highly selective, and sensitive approach for oligomer analysis, which is significant for amyloid protein research and related disease diagnosis.

Associations of amyloid-β oligomers and plaques with neuropathology in the App NL-G-F mouse.

Amyloid-β pathology and neurofibrillary tangles lead to glial activation and neurodegeneration in Alzheimer's disease. In this study, we investigated the relationships between the levels of amyloid-β oligomers, amyloid-β plaques, glial activation and markers related to neurodegeneration in the App NL-G-F triple mutation mouse line and in a knock-in line homozygous for the common human amyloid precursor protein (App hu mouse). The relationships between neuropathological features were characterized with immunohistochemistry and imaging mass cytometry. Markers assessing human amyloid-β proteins, microglial and astrocytic activation and neuronal and synaptic densities were used in mice between 2.5 and 12 months of age. We found that amyloid-β oligomers were abundant in the brains of App hu mice in the absence of classical amyloid-β plaques. These brains showed morphological changes consistent with astrocyte activation but no evidence of microglial activation or synaptic or neuronal pathology. In contrast, both high levels of amyloid-β oligomers and numerous plaques accumulated in App NL-G-F mice in association with substantial astrocytic and microglial activation. The increase in amyloid-β oligomers over time was more strongly correlated with astrocytic than with microglia activation. Spatial analyses suggested that activated microglia were more closely associated with amyloid-β oligomers than with amyloid-β plaques in App NL-G-F mice, which also showed age-dependent decreases in neuronal and synaptic density markers. A comparative study of the two models highlighted the dependence of glial and neuronal pathology on the nature and aggregation state of the amyloid-β peptide. Astrocyte activation and neuronal pathology appeared to be more strongly associated with amyloid-β oligomers than with amyloid-β plaques, although amyloid-β plaques were associated with microglia activation.

Unraveling Alzheimer’s: Exploring the Gut Microbiota–Brain Axis as a New Frontier in Understanding

The gut microbiota (GM) communicates with the brain via biochemical signaling constituting the gut–brain axis, which significantly regulates the body’s physiological processes. The GM dysbiosis can impact the digestive system and the functioning of the central nervous system (CNS) linked to the onset of neurodegenerative diseases. In this review, the scientific data compiled from diverse sources primarily emphasize the neuropathological characteristics linked to the accumulation of modified insoluble proteins (such as β-Amyloid peptides and hyperphosphorylated tau proteins) in Alzheimer’s Disease (AD) and the potential impact of gut microbiota (GM) on AD susceptibility or resilience. The specific GM profile of human beings may serve as an essential tool for preventing or progressing neurodegenerative diseases like AD. This review focuses mainly on the effect of gut microfauna on the gut–brain axis in the onset and progression of AD. The GM produces various bioactive molecules that may serve as proinflammatory or anti-inflammatory signaling, contributing directly or indirectly to the repression or progression of neurodegenerative disorders by modulating the response of the brain axis. Human studies must focus on further understanding the gut–brain axis and venture to clarify microbiota-based therapeutic strategies for AD.

Computational analysis of hydrogen bonds network dynamics in the water layers surrounding Aβ(1-42) and Aβ(1-40) peptide dimers

The amyloid-β peptide (Aβ) dimer is involved in the development of Alzheimer’s disease through forming amyloid plaques. Aβ(1-40) and Aβ(1-42) are the most common and poisonous species causing Alzheimer’s disease. They form homogeneous dimers containing two similar peptides and heterogeneous dimers containing different ones. The low molecular weight, fast dynamics, and varying compositions of these dimers make it difficult to study them by conventional experimental methods. Hence, we clarify the effect of the diversity of the Aβ dimers on the structure of the water molecules around the peptides by the molecular dynamics (MD) simulation method in this study. MD simulations of the Aβ(1-40) and Aβ(1-42) monomers are also performed for the comparison. The calculations are repeated in the presence of dimethyl sulfoxide (DMSO). The water molecules positioned at distances of 0.5, 0.75, 1, 1.25, and 1.5 nm from the protein were chosen to investigate the distribution and dynamics of hydrogen bonds in the layers surrounding the peptide. The results show that the heterogeneity of the dimer system increases the percentage of hydrogen (H) atoms not involved in any water-water hydrogen bonds around the peptides in the different layers. While it decreases the percentage of H atoms involved in one and two water-water hydrogen bonds. The DMSO presence reduces the percentage of H atoms involved in two hydrogen bonds in the systems containing a mixture of water and DMSO. The average interaction energy of the dimers demonstrates the enhanced interactions of the two peptides in water in comparison with that in the mixture of water and DMSO. The behavior of the water molecules around the heterogeneous dimer is very similar to that around the Aβ(1-42) homogeneous dimer.

Cannabidiol protects mouse hippocampal neurons from neurotoxicity induced by amyloid β-peptide25–35

Alzheimer's disease (AD), the most prevalent form of dementia worldwide, is a significant health concern, according to the World Health Organization (WHO). The neuropathological diagnostic criteria for AD are based on the deposition of amyloid-β peptide (Aβ) and the formation of intracellular tau protein tangles. These proteins are associated with several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, reduced neuronal viability, and cell death. In this context, our study focuses on the potential therapeutic use of cannabidiol (CBD), a non-psychotropic cannabinoid with antioxidant and anti-inflammatory effects. We aim to evaluate CBD's neuroprotective role, particularly in protecting hippocampal neurons from Aβ25–35-induced toxicity. Our findings indicate that CBD significantly improves cell viability and decreases levels of lipid peroxidation and oxidative stress. The results demonstrate that CBD possesses a robust potential to rescue cells from induced neurotoxicity through its antioxidant properties. Additionally, the neuroprotective effect of CBD may be associated with the modulation of the endocannabinoid system. These findings suggest that CBD could be a promising compound for adjuvant treatments in neurodegenerative processes triggered by amyloid-β peptide.

Aggregation Mechanisms and Molecular Structures of Amyloid-β in Alzheimer's Disease.

Amyloid plaques are a major pathological hallmark involved in Alzheimer's disease and consist of deposits of the amyloid-β peptide (Aβ). The aggregation process of Aβ is highly complex, which leads to polymorphous aggregates with different structures. In addition to aberrant aggregation, Aβ oligomers can undergo liquid-liquid phase separation (LLPS) and form dynamic condensates. It has been hypothesized that these amyloid liquid droplets affect and modulate amyloid fibril formation. In this review, we briefly introduce the relationship between stress granules and amyloid protein aggregation that is associated with neurodegenerative diseases. Then we highlight the regulatory role of LLPS in Aβ aggregation and discuss the potential relationship between Aβ phase transition and aggregation. Furthermore, we summarize the current structures of Aβ oligomers and amyloid fibrils, which have been determined using nuclear magnetic resonance (NMR) and cryo-electron microscopy (cryo-EM). The structural variations of Aβ aggregates provide an explanation for the different levels of toxicity, shed light on the aggregation mechanism and may pave the way towards structure-based drug design for both clinical diagnosis and treatment.

Molecular Insight into the Effect of HIV-TAT Protein on Amyloid-β Peptides.

Increased deposition of amyloid-β (Aβ) plaques in the brain is a frequent pathological feature observed in human immunodeficiency virus (HIV)-positive patients. Emerging evidence indicates that HIV regulatory proteins, particularly the transactivator of transcription (TAT) protein, could interact with Aβ peptide, accelerating the formation of Aβ plaques in the brain and potentially contributing to the onset of Alzheimer's disease in individuals with HIV infection. Nevertheless, the molecular mechanisms underlying these processes remain unclear. In the present study, we have used long all-atom molecular dynamics simulations to probe the direct interactions between the TAT protein and Aβ peptide at the molecular level. Sampling over 28.0 μs, our simulations show that TAT protein induces a shift in the Aβ monomer ensemble toward elongated conformations, exposing aggregation-prone regions on the surface and thereby inducing subsequent aggregation. TAT protein also appears to enhance the stability of preformed Aβ fibrils, while increasing the β-sheet content within these fibrils. Our atomistically detailed simulations qualitatively agree with previous in vitro and in vivo studies. Importantly, our simulations identify key interactions between Aβ and the TAT protein that drive the Aβ aggregation process and stabilize the preformed Aβ aggregates, which are particularly challenging to obtain through current experimental techniques.

Molecular mechanism of substrate recognition and cleavage by human γ-secretase.

Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step size of three residues. To elucidate the underlying mechanism, we determined the atomic structures of human γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43. In all cases, the substrate displays the same structural features: a transmembrane α-helix, a three-residue linker, and a β-strand that forms a hybrid β-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate β-strand. Each cleavage is followed by unwinding and translocation of the substrate α-helix by one turn and the formation of a new β-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by γ-secretase.

Rational Design of Dual-Functionalized Gd@C82 Nanoparticles to Relieve Neuronal Cytotoxicity in Alzheimer's Disease via Inhibition of Aβ Aggregation.

The accumulation of amyloid-β (Aβ) peptides is a major hallmark of Alzheimer's disease (AD) and plays a crucial role in its pathogenesis. Particularly, the structured oligomeric species rich in β-sheet formations were implicated in neuronal organelle damage. Addressing this formidable challenge requires identifying candidates capable of inhibiting peptide aggregation or disaggregating preformed oligomers for effective antiaggregation-based AD therapy. Here, we present a dual-functional nanoinhibitor meticulously designed to target the aggregation driving force and amyloid fibril spatial structure. Leveraging the exceptional structural stability and facile tailoring capability of endohedral metallofullerene Gd@C82, we introduce desired hydrogen-binding sites and charged groups, which are abundant on its surface for specific designs. Impressively, these designs endow the resultant functionalized-Gd@C82 nanoparticles (f-Gd@C82 NPs) with high capability of redirecting peptide self-assembly toward disordered, off-pathway species, obstructing the early growth of protofibrils, and disaggregating the preformed well-ordered protofibrils or even mature Aβ fibrils. This results in considerable alleviation of Aβ peptide-induced neuronal cytotoxicity, rescuing neuronal death and synaptic loss in primary neuron models. Notably, these modifications significantly improved the dispersibility of f-Gd@C82 NPs, thus substantially enhancing its bioavailability. Moreover, f-Gd@C82 NPs demonstrate excellent cytocompatibility with various cell lines and possess the ability to penetrate the blood-brain barrier in mice. Large-scale molecular dynamics simulations illuminate the inhibition and disaggregation mechanisms. Our design successfully overcomes the limitations of other nanocandidates, which often overly rely on hydrophobic interactions or photothermal conversion properties, and offers a viable direction for developing anti-AD agents through the inhibition and even reversal of Aβ aggregation.

CONFORMATIONAL PARTICULARITIES OF A(25-35) PEPTIDE DETERMINED BY INFRARED SPECTROSCOPY

The Alzheimer’s amyloid-β (25-35) peptide retains the toxicity and ability to aggregate of the amyloid-(1-40) peptide. The study of the conformational properties of Aβ (25-35) peptide in its soluble monomeric form can play an essential role in determining the mechanism of oligomerization. In this study, we probed the secondary structure of a soluble Aβ (25-35) peptide in water solution at physiological conditions (pH 7.4). We have used Fourier Transformed Infrared Spectroscopy (FTIR) to examine the secondary structure of this peptide. The amide I bands of A (25-35) obtained from transmission-FTIR spectra consists of one main band at 1658 cm-1, at both concentrations used (200 M and 1 mM). This band show us that A (25-35) in aqueous solution was mostly organized into a -helical structure (48%). The contribution of the unordered structure was found to be about 12%. The proportion of -sheet and -turn structures are slightly lower, 12-15% and 13-14%, respectively for both concentrations. FTIR spectra of the peptide in water solution (100 µM) after incubation for 12h showed Aβ peptide conformation is critically dependent on the environmental conditions used.

Nanodisc Reconstitution and Characterization of Amyloid-β Precursor Protein C99.

Amyloid precursor protein (APP) plays a pivotal role in the pathology of Alzheimer's disease (AD). Since the fragmentation of the membrane-bound APP that results in the production of amyloid-β peptides is the starting point for amyloid toxicity in AD, it is important to investigate the structure and dynamics of APP in a near-native lipid-bilayer environment. However, the reconstitution of APP into a stable and suitable membrane-mimicking lipid environment is a challenging task. In this study, the 99-residue C-terminal domain of APP is successfully reconstituted into polymer nanodiscs and characterized using size-exclusion chromatography, mass spectrometry, solution NMR, and magic-angle spinning solid-state NMR. In addition, the feasibility of using lipid-solubilizing polymers for isolating and characterizing APP in the native Escherichia. coli membrane environment is demonstrated.

Lutein from Chicken Eggs Prevents Amyloid β-Peptide Aggregation In Vitro and Amyloid β-Induced Inflammation in Human Macrophages (THP-1).

Epidemiological studies predict that chicken eggs contain constituents other than proteins that prevent Alzheimer's disease. This study screened for constituents that inhibit the aggregation of amyloid β peptide (Aβ)1-42 and elucidated their mechanisms to explore the active components of chicken eggs. Thioflavin T assays and transmission electron microscopy observations showed that arachidonic acid (ARA), lysophosphatidylcholine, lutein (LTN), palmitoleic acid, and zeaxanthin inhibited Aβ aggregation. Among these, ARA and LTN showed the highest activity. Photoinduced cross-linking of unmodified protein assays and infrared absorption spectrometry measurements showed that LTN strongly inhibited highly toxic Aβ1-42 protofibril formation. Furthermore, LTN suppressed Aβ1-42-induced IL 1B and TNF expression in human macrophage-like cells. In summary, LTN plays a crucial role in the AD-preventive effect of chicken eggs by suppressing Aβ1-42 aggregation and Aβ1-42-induced inflammation.

Alzheimer's disease: part 2 - the present.

Based on my work as a clinical neurologist with more than 50 years of experience in caring for patients with Alzheimer's disease (AD), I focus, in this review article, on the disease's two fundamental aspects for the doctor: diagnosis and treatment. The 1984 diagnostic criteria had been stable for more than a quarter of a century when it was replaced in 2011. Since then, there have been many discoveries, especially of biomarkers that have a heavy impact on the diagnosis of AD. Recently, AD biomarkers have become available in plasma, which certainly will cause a major change in the diagnosis of biological AD, a term that still needs care and information to society before being used in clinical practice. Three monoclonal antibodies against β-amyloid peptide have also been recently approved, and two of these have shown a small but statistically significant effect on clinical outcome. These monoclonal antibodies have had a greater effect on the reduction of amyloid plaques in the brain assessed by positron emission tomography (PET), and on the concentration of biomarkers in the cerebrospinal fluid (β-amyloid peptide with 42 amino acids and hyperphosphorylated tau protein) than in the neuropsychological and functional assessments. Even this small clinical effect will be encouraging for the development of new research, particularly helped by the greater ease of diagnosis and monitoring of the evolution of AD pathophysiology with plasma biomarkers. Recently, new diagnostic criteria for AD were presented by the Alzheimer's Association, causing controversy about their use in clinical practice.

Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein

The aggregation of Amyloid-β (Aβ) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with Aβ species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ1 receptor chaperone and as σ1 agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ1 receptor. We report that Amylovis-201 is a potent σ1 agonist by several in silico, in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ1 receptors. Furthermore, we show for the first time that classical σ1 receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate Aβ25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting Aβ25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ1 receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.

Amino-terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains.

The aggregation and deposition of amyloid-β (Aβ) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full-length Aβ peptides starting with an aspartate residue in position 1, both N-terminally truncated and elongated Aβ peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N-terminally truncated Aβ4-x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N-terminally elongated Aβ peptides. We used cell-free and cell-based assays in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N-terminally elongated Aβ peptide variants. Antibodies against these Aβ variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples. In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N-terminal to Asp-(1) in the Aβ peptide sequence between residues Glu-(-7) and Ile-(-6) as well as Glu-(-4) and Val-(-3), resulting in the release of N-terminally elongated Aβ-6-x and Aβ-3-x peptides, of which the latter serve as a component in a promising Aβ-based plasma biomarker. Aβ-6/-3-40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of Aβ-6/-3-x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N-terminally elongated Aβ-6/-3-x peptides. The current findings implicate ADAMTS4 in both the pathological process of Aβ peptide aggregation and in the early detection of amyloid pathology in AD.

Evaluation of the Xtb Semiempirical Method for the Prediction of Antioxidant Properties in Alzheimer’s Disease: Salen-Type Ligands

Alzheimer’s disease (AD) stands as the predominant form of dementia, accounting for up to 70% of all cases worldwide. AD is a complex disease with various contributing factors. Evidence suggests that the metalliccomplexes formed by the β-amyloid peptide (Aβ) and extraneuronal copper can catalyze the generation ofreactive oxygen species, consequently increasing oxidative stress and contributing to the decline of neurons. This interaction underscores the significance of bioavailable copper as a crucial redox-active target in exploring protocols for multifunctional agents in AD treatment. In the field of computational chemistry, density functional theory (DFT) is widely accepted as a standard method across different disciplines. Despite this, DFT presents computational challenges, particularly in screening extensive molecular sets during the initial phases of drug research. Recent advances in semiempirical quantum mechanical methods (SQM) offer a promising alternative, providing rapid molecular geometry optimization and approximate estimation of thermodynamical properties, being at least two orders of magnitude faster than traditional DFT calculations. In this work, we present an evaluation of the GFNn-xTB SQM methods in the rapid screening of antioxidant properties in AD, performed on a set of salen ligands by calculating the standard reduction potentials of their copper complexes as key property. Results show that the implementation of GFNn-xTB SQM calculations before DFT evaluations is

Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes.

Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls. Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.