Accumulation Of Amyloid-β Peptide Research Articles

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.

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.

Modeling the Effects of Cell Stress and Ca2+ Dysregulation on the Crosstalk Between Apoptosis and Autophagy in Neurodegenerative Diseases

BACKGROUND: Apoptosis is a highly regulated and irreversible process of cell death, while autophagy maintains cellular homeostasis by degrading and recycling cytoplasmic components, such as aggregated and damaged proteins (Elmore, 2007; Glick et al., 2010). Dysregulation of both processes is observed in neurodegenerative diseases (NDs) (Ghavami et al., 2014). For example, in Alzheimer’s disease (AD), accumulation of amyloid-β peptides is attributed to dysregulated autophagy (Han et al., 2020). Dysregulated autophagy can further induce apoptosis and neurodegeneration (Chung et al., 2018). Although studies have focused on signaling pathways involved in apoptosis and autophagy extensively in other cell types, an effective framework to clarify their interplay in the nervous system is lacking. Here we develop a simplified network model of the key pathways involved in apoptosis and autophagy to study their interplay and dysregulation in NDs. Specifically, we model triggers such as cell stress and Ca2+ dysregulation implicated in aging and NDs and simulate their effects on cell fate. Although much of the empirical support to model development came from studies in other cell types, our integrative framework of the ubiquitous and non-cell autonomous pathways can offer deeper insights into the pathophysiology in NDs. METHODS: Ordinary differential equations (ODEs) were used to model the network of molecular compartments, and the rates of change in their abundances and interactions. The interconnections between these compartments, for example, the inhibitory role of caspases on autophagy-inducing Beclin-1(BECN1), are validated in empirical work and adopted in previous modeling studies (Bogdał et al., 2013; Fan and Zong, 2013; Mariño et al., 2014; Tavassoly et al., 2015; Wirawan et al., 2010; Yin et al., 2017). MATLAB was used to code and simulate the model; ode45 was the numerical integration method of choice. RESULTS: We developed an integrative framework for the signaling pathways of apoptosis and autophagy. Our model adapted and merged three previously reported dynamic network models (Bogdal et al., 2013; Tavassoly et al., 2015; Yin et al., 2017) which also included pathways relevant to NDs. A hypothetical cell stress input and cytosolic Ca2+ concentration in our network model represent extrinsic and intrinsic triggers respectively. Using such a computational approach, we are investigating the multiplexing role of Beclin 1 protein (part of Bcl-2 protein family), mTOR (mammalian target of rapamycin) kinase and JNK (Jun N-terminal kinase) in the synergy between autophagy and apoptosis. Simulation experiments are underway to predict the mechanisms of cell vulnerability versus resilience implicated in NDs involving these pathways. CONCLUSION: Our network provides a framework based on which experiments can be designed to validate model predictions and better understand the dynamic processes involved in NDs. Although NDs are complex and chronic, understanding the effects of common triggers such as cell stress and disrupted Ca2+ homeostasis on cell fate determination is critical to slow ND progression. Therefore, our study delineating the dynamic crosstalk between apoptosis and autophagy offers crucial insights into ND pathophysiology and suggests specific protein targets within these key common pathways. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Beta-amyloid plaque deposits and increased tau protein in the early diagnosis of alzheimer’s disease: the importance of physical activity in the prevention and evolution of the patient

In recent years, it has become clear that the β-amyloid (Aβ) component of senile plaques may be the key molecule in the pathology of Alzheimer's disease (AD). However, the origin and site of Aβ's neurotoxic action are still the subject of controversy. The precursor of the β-amyloid peptide is the β-amyloid precursor protein, which is predominantly neuronal. The hypothesis is that intraneuronal dysregulation of Amyloid Precursor Protein (APP) leads to the accumulation of Aβ peptides in intracellular compartments. This accumulation impairs the trafficking of APP, which initiates a cascade of pathological changes and causes the degeneration of pyramidal neurons. The increased secretion of Aβ as a function of stressed neurons and degenerated neuron remnants provides seeds for extracellular Aβ aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia. The benefits of physical exercise to reduce low-grade inflammation and improve cognitive function have become a growing field of interest. Epidemiological research has shown that a sedentary lifestyle intensifies the processes of disability and dependence, and also increases the incidence of chronic diseases. Physical exercise has been inversely associated with high levels of different inflammatory markers. It plays a neurotrophic role, capable of promoting a reduction in the accumulation of β-amyloid peptide and the hyperphosphorylation of tau protein, being an important alternative pathway for reducing the degenerative process, which does not result in the release of pro-inflammatory factors, as well as helping to reduce the levels of pro-inflammatory cytokines and improve peripheral concentrations.

Effect of caffeine on the aggregation of amyloid-β-A 3D RISM study.

Alzheimer's disease is a detrimental neurological disorder caused by the formation of amyloid fibrils due to the aggregation of amyloid-β peptide. The primary therapeutic approaches for treating Alzheimer's disease are targeted to prevent this amyloid fibril formation using potential inhibitor molecules. The discovery of such inhibitor molecules poses a formidable challenge to the design of anti-amyloid drugs. This study investigates the effect of caffeine on dimer formation of the full-length amyloid-β using a combined approach of all-atom, explicit water molecular dynamics simulations and the three-dimensional reference interaction site model theory. The change in the hydration free energy of amyloid-β dimer, with and without the inhibitor molecules, is calculated with respect to the monomeric amyloid-β, where the hydration free energy is decomposed into energetic and entropic components, respectively. Dimerization is accompanied by a positive change in the partial molar volume. Dimer formation is spontaneous, which implies a decrease in the hydration free energy. However, a reverse trend is observed for the dimer with inhibitor molecules. It is observed that the negatively charged residues primarily contribute for the formation of the amyloid-β dimer. A residue-wise decomposition reveals that hydration/dehydration of the side-chain atoms of the charged amino acid residues primarily contribute to dimerization.

Novel 6-alkyl-bridged 4-arylalkylpiperazin-1-yl derivatives of azepino[4,3-b]indol-1(2H)-one as potent BChE-selective inhibitors showing protective effects against neurodegenerative insults

Due to the putative role of butyrylcholinesterase (BChE) in regulation of acetylcholine levels and functions in the late stages of the Alzheimer's disease (AD), the potential of selective inhibitors (BChEIs) has been envisaged as an alternative to administration of acetylcholinesterase inhibitors (AChEIs). Starting from our recent findings, herein the synthesis and in vitro evaluation of cholinesterase (ChE) inhibition of a novel series of some twenty 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one derivatives, bearing at the indole nitrogen diverse alkyl-bridged 4-arylalkylpiperazin-1-yl chains, are reported. The length of the spacers, as well as the type of arylalkyl group affected the enzyme inhibition potency and BChE/AChE selectivity. Two compounds, namely 14c (IC50 = 163 nM) and 14d (IC50 = 65 nM), bearing at the nitrogen atom in position 6 a n-pentyl- or n-heptyl-bridged 4-phenethylpiperazin-1-yl chains, respectively, proved to be highly potent mixed-type inhibitors of both equine and human BChE isoforms, showing more than two order magnitude of selectivity over AChE. The study of binding kinetics through surface plasmon resonance (SPR) highlighted differences in their BChE residence times (8 and 47 s for 14c and 14d, respectively). Moreover, 14c and 14d proved to hit other mechanisms known to trigger neurodegeneration underlying AD and other CNS disorders. Unlike 14c, compound 14d proved also capable of inhibiting by more than 60% the in vitro self-induced aggregation of neurotoxic amyloid-β (Aβ) peptide at 100 μM concentration. On the other hand, 14c was slightly better than 14d in counteracting, at 1 and 10 μM concentration, glutamate excitotoxicity, due to over-excitation of NMDA receptors, and hydrogen peroxide-induced oxidative stress assessed in neuroblastoma cell line SH-SY5Y. This paper is dedicated to Prof. Marcello Ferappi, former dean of the Faculty of Pharmacy of the University of Bari, in the occasion of his 90th birthday.

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs.

Alzheimer's disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42) peptides, Mdr1 and APP(amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9-40weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40, and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20weeks old toward 40weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.

Astemizole, a Second-Generation Histamine H1-Receptor Antagonist, Did Not Attenuate the Aggregation Process of α-Synuclein In Vitro.

The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson's disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer's disease-related amyloid-β (Aβ) peptide and has inhibitory activity on the human prion protein PrPSc. We hypothesized that the proposed preclinical benefits of astemizole on PD can be associated with the attenuation of pathological α-synuclein (α-syn) aggregation. We tested the effects of astemizole on the fibrillation processes of amyloid peptides using thioflavin T aggregation monitoring, Congo red spectral analysis, cell viability study, and transmission electron microscopic imaging. We found that astemizole did not inhibit α-syn aggregation in vitro even at a high molar ratio but inhibited the assembly of Aβ aggregates. Our results suggest that the inhibitory effect of astemizole on amyloid formation is target-protein selective, and the proposed beneficial effects of this compound observed in translational PD models might not be due to its ameliorating effects on α-syn aggregation.

Molecular Insights into the Inhibition and Disaggregation Effects of EGCG on Aβ40 and Aβ42 Cofibrillation.

The misfolding and aggregation of amyloid-β (Aβ) peptides play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Aβ40 and Aβ42, the two primary isoforms of Aβ, can not only self-aggregate into homogeneous aggregates but also coaggregate to form mixed fibrils. Epigallocatechin-3-gallate (EGCG), a prominent tea polyphenol, has shown the capability to prevent the self-aggregation of Aβ40 and Aβ42 peptides and disaggregate their homogeneous fibrils. However, its effects on the cofibrillation of Aβ40 and Aβ42 have not yet been explored. Here, we employed molecular dynamic simulations to investigate the effects of EGCG on the coaggregation of Aβ40 and Aβ42, as well as on their mixed fibril. Our findings indicated that EGCG effectively inhibits the codimerization of Aβ40 and Aβ42 primarily by impeding the interchain interaction between the two isoforms. The key binding sites for EGCG on Aβ40 and Aβ42 are the polar residues and aromatic residues, engaging in hydrogen-bond , π-π, and cation-π interactions with EGCG. Additionally, EGCG disaggregates the Aβ40-Aβ42 mixed fibril by reducing its long-range interaction through similar binding sites and interactions as those between EGCG and Aβ40-Aβ42 heterodimers. Our research reveals the comprehensive inhibition and disaggregation effects of EGCG on the cofibrillation of Aβ isoforms, which provides further support for the development of EGCG as an effective antiaggregation agent for AD.

In Silico Exploration of APOE4 Inhibitors: Molecular Docking and ADMET Profiling for Alzheimer's Therapy

Background: Alzheimer's disease (AD), a prevalent neurodegenerative disorder, poses significant challenges to healthcare systems worldwide. The aggregation of Amyloid-β peptide and the presence of apolipoprotein E4 (apoE4) are recognized as central factors in AD pathogenesis. Despite the availability of FDA-approved drugs, there remains a dire need for more effective and targeted treatments to combat this disease. The advent of in silico methodologies offers a promising avenue for accelerating the drug discovery process, providing a cost-effective and efficient means to screen for potential therapeutic agents. Objective: This study aimed to identify and evaluate potential inhibitors of apoE4 using in silico drug discovery methods. By targeting the interaction domain of apoE4, the study sought to discover compounds capable of reducing beta-amyloid aggregation, thus offering a novel approach to AD therapy. Methods: Computational techniques, including the Lipinski Rule of Five and ADMET filtering, were employed to screen a dataset of 80 chemical inhibitors retrieved from the NCBI database. Molecular docking was performed to assess the binding affinities and orientations of the compounds to apoE4, utilizing Phyre2 for 3D structure prediction and AutoDock Vina for docking simulations. The selection criteria for lead compounds were based on their binding energy, hydrogen bonding interactions, and compliance with drug-like properties. Results: Out of the initial 80 compounds screened, 15 were excluded based on the Lipinski Rule of Five, and an additional 43 were deemed unsuitable following ADMET analysis. Molecular docking identified two compounds, taxifolin and luteolin, exhibiting superior binding affinities to apoE4, with taxifolin showing the lowest binding energy of -7.4 kcal/mol and the highest number of hydrogen bonds in one of its conformations. Conclusion: The study successfully leveraged in silico methods to identify taxifolin and luteolin as potent inhibitors of apoE4, highlighting the potential of computational drug discovery in developing novel AD therapies. These findings pave the way for future experimental validation and clinical trials to assess the therapeutic efficacy and safety of these compounds in treating Alzheimer's disease.

Development of Neuroprotective Agents for the Treatment of Alzheimer's Disease using Conjugates of Serotonin with Sesquiterpene Lactones.

Sesquiterpene lactones are secondary plant metabolites with a wide variety of biological activities. The process of lactone conjugation to other pharmacophores can increase the efficacy and specificity of the conjugated agent effect on molecular targets in various diseases, including brain pathologies. Derivatives of biogenic indoles, including neurotransmitter serotonin, are of considerable interest as potential pharmacophores. Most of these compounds have neurotropic activity and, therefore, can be used in the synthesis of new drugs with neuroprotective properties. The aim of this experimental synthesis was to generate potential treatment agents for Alzheimer's disease using serotonin conjugated with natural sesquiterpene lactones. Three novel compounds were obtained via the Michael reaction and used for biological testing. The obtained conjugates demonstrated complex neuroprotective activities. Serotonin conjugated to isoalantolactone exhibited strong antioxidant and mitoprotective activities. The agent was also found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), prevent the aggregation of β-amyloid peptide 1-42, and protect SH-SY5Y neuroblastoma cells from neurotoxins such as glutamate and H2O2. In a transgenic animal model of Alzheimer's disease (5xFAD line), the conjugated agent restored declined cognitive functions and improved learning and memory. In conclusion, the obtained results indicate that serotonin conjugates to sesquiterpene lactones are promising agents for the treatment of symptoms associated with Alzheimer's disease.

Impact of nanoplastics on Alzheimer ’s disease: Enhanced amyloid-β peptide aggregation and augmented neurotoxicity

Nanoplastics, widely existing in the environment and organisms, have been proven to cross the blood-brain barrier, increasing the incidence of neurodegenerative diseases like Alzheimer’s disease (AD). However, current studies mainly focus on the neurotoxicity of nanoplastics themselves, neglecting their synergistic effects with other biomolecules and the resulting neurotoxicity. Amyloid β peptide (Aβ), which triggers neurotoxicity through its self-aggregation, is the paramount pathogenic protein in AD. Here, employing polystyrene nanoparticles (PS) as a model for nanoplastics, we reveal that 100 pM PS nanoparticles significantly accelerate the nucleation rate of two Aβ subtypes (Aβ40 and Aβ42) at low concentrations, promoting the formation of more Aβ oligomers and leading to evident neurotoxicity. The hydrophobic surface of PS facilitates the interaction of hydrophobic fragments between Aβ monomers, responsible for the augmented neurotoxicity. This work provides consequential insights into the modulatory impact of low-dose PS on Aβ aggregation and the ensuing neurotoxicity, presenting a valuable foundation for future research on the intricate interplay between environmental toxins and brain diseases.

Natural flavonoid hesperetin blocks amyloid β-protein fibrillogenesis, depolymerizes preformed fibrils and alleviates cytotoxicity caused by amyloids.

The aggregation of β-amyloid (Aβ) peptides to form amyloid plaques is one of the primary hallmarks for Alzheimer's disease (AD). Dietary flavonoid supplements containing hesperetin have an ability to decline the risk of developing AD, but the molecular mechanism is still unclear. In this work, hesperetin, a flavanone abundant in citrus fruits, has been proven to prevent the formation of Aβ aggregates and depolymerized preformed fibrils in a concentration-dependent fashion. Hesperetin inhibited the conformational conversion from the natural structure to a β-sheet-rich conformation. It was found that hesperetin significantly reduced the cytotoxicity and relieved oxidative stress eventuated by Aβ aggregates in a concentration-dependent manner. Additionally, the beneficial effects of hesperetin were confirmed in Caenorhabditis elegans, including the inhibition of the formation and deposition of Aβ aggregates and extension of their lifespan. Finally, the results of molecular dynamics simulations showed that hesperetin directly interacted with an Aβ42 pentamer mainly through strong non-polar and electrostatic interactions, which destroyed the structural stability of the preformed pentamer. To summarize, hesperetin exhibits great potential as a prospective dietary supplement for preventing and improving AD.

Aggregation, structure and water permeability of membrane-embedded helical Aβ oligomers.

It is widely recognized that membranes can facilitate the aggregation of amyloid-β (Aβ) peptides, while Aβ can in turn cause membrane damage. Many studies focus on the peptide-membrane interactions of Aβ oligomers with β-rich structures. However, the exact aggregation and toxicity mechanism of the membrane-embedded helical Aβ oligomers remain ambiguous. Herein, the molecular dynamics simulations were performed on membrane-embedded helical Aβ42 peptides. Initiated by eight Aβ42 monomers embedded in a lipid bilayer, the monomers aggregate into oligomers with stable transmembrane helix structures. With the aggregation of peptides, the membrane perturbations caused by Aβ aggregates decrease. The molecular architectures of oligomers were characterized and a helix-rich octamer stabilized by an annular network of hydrogen bonds was observed. The oligomers demonstrate the capability to assist transmembrane water transport. Our study may provide new insights for the investigation of transmembrane Aβ oligomers.

Click synthesis of dendronized malonates for the preparation of amphiphilic dendro[60]fullerenes.

Fullerene C60 and its malonate derivatives, produced via the Bingel-Hirsch reaction, have displayed promising properties against various diseases. These molecules have great therapeutic potential, but their broad use has been limited due to poor aqueous solubility and toxicity caused by accumulation. In this study, we synthesized new malonates and malonamides attached to first- and second-generation polyester dendrons using click chemistry (CuAAC). These dendrons were then linked at C60 through the Bingel-Hirsch reaction, resulting in an amphiphilic system that retains the hydrophobic nature of C60. The dendronized malonate derivatives showed good reaction yields for the Bingel-Hirsch mono-adducts and were easier to work with than the corresponding malonamides. However, the malonamide derivatives, which were obtained through a multistep reaction sequence, showed moderate yields in the Bingel-Hirsch reaction. Surprisingly, removing acetonide protecting groups from dendritic architectures was more challenging than anticipated, likely due to product decomposition. Only the corresponding free malonate derivatives 25 and 26 were obtained, but in a low yield due to decomposition under the reaction conditions. Meanwhile, it was not possible to obtain the corresponding malonamide derivatives 27 and 28. Currently, efforts are being made to improve the production of the desired molecules and to design new synthesis routes that allow direct access to the desired poly-hydroxylated derivatives. These derivatives will be evaluated as multitarget ligands against Alzheimer's disease, through their use as inhibitors of amyloid β-peptide aggregation, acetylcholinesterase modulators, and antioxidants.

A Potential Role for the Ketogenic Diet in Alzheimer's Disease Treatment: Exploring Pre-Clinical and Clinical Evidence.

Given the remarkable progress in global health and overall quality of life, the significant rise in life expectancy has become intertwined with the surging occurrence of neurodegenerative disorders (NDs). This emerging trend is poised to pose a substantial challenge to the fields of medicine and public health in the years ahead. In this context, Alzheimer's disease (AD) is regarded as an ND that causes recent memory loss, motor impairment and cognitive deficits. AD is the most common cause of dementia in the elderly and its development is linked to multifactorial interactions between the environment, genetics, aging and lifestyle. The pathological hallmarks in AD are the accumulation of β-amyloid peptide (Aβ), the hyperphosphorylation of tau protein, neurotoxic events and impaired glucose metabolism. Due to pharmacological limitations and in view of the prevailing glycemic hypometabolism, the ketogenic diet (KD) emerges as a promising non-pharmacological possibility for managing AD, an approach that has already demonstrated efficacy in addressing other disorders, notably epilepsy. The KD consists of a food regimen in which carbohydrate intake is discouraged at the expense of increased lipid consumption, inducing metabolic ketosis whereby the main source of energy becomes ketone bodies instead of glucose. Thus, under these dietary conditions, neuronal death via lack of energy would be decreased, inasmuch as the metabolism of lipids is not impaired in AD. In this way, the clinical picture of patients with AD would potentially improve via the slowing down of symptoms and delaying of the progression of the disease. Hence, this review aims to explore the rationale behind utilizing the KD in AD treatment while emphasizing the metabolic interplay between the KD and the improvement of AD indicators, drawing insights from both preclinical and clinical investigations. Via a comprehensive examination of the studies detailed in this review, it is evident that the KD emerges as a promising alternative for managing AD. Moreover, its efficacy is notably enhanced when dietary composition is modified, thereby opening up innovative avenues for decreasing the progression of AD.

Aggregation Dynamics Characteristics of Seven Different Aβ Oligomeric Isoforms-Dependence on the Interfacial Interaction.

The aggregation of β-amyloid (Aβ) peptides has been confirmed to be associated with the onset of Alzheimer's disease (AD). Among the three phases of Aβ aggregation, the lag phase has been considered to be the best time for early Aβ pathological deposition clinical intervention and prevention for potential patients with normal cognition. Aβ peptide exists in various lengths in vivo, and Aβ oligomer in the early lag phase is neurotoxic but polymorphous and metastable, depending on Aβ length (isoform), molecular weight, and specific phase, and therefore hardly characterized experimentally. To cope with the problem, molecular dynamics simulation was used to investigate the aggregation process of five monomers for each of the seven common Aβ isoforms during the lag phase. Results showed that Aβ(1-40) and Aβ(1-38) monomers aggregated faster than their truncated analogues Aβ(4-40) and Aβ(4-38), respectively. However, the aggregation rate of Aβ(1-42) was slower than that of its truncated analogues Aβ(4-42) rather than that of Aβpe(3-42). More importantly, Aβ(1-38) is first predicted as more likely to form stable hexamer than the remaining five Aβ isoforms, as Aβ(1-42) does. It is hydrophobic interaction mainly (>50%) from the interfacial β1 and β2 regions of two reactants, pentamer and monomer, aggregated by Aβ(1-38)/Aβ(1-42) rather than by other Aβ isoforms, that drives the hexamer stably as a result of the formation of the effective hydrophobic collapse. This paper provides new insights into the aggregation characteristics of Aβ with different lengths and the conditions necessary for Aβ to form oligomers with a high molecular weight in the early lag phase, revealing the dependence of Aβ hexamer formation on the specific interfacial interaction.

Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aβ on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAβ). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAβ) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aβ levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD.

Nascent Aβ42 Fibrillization in Synaptic Endosomes Precedes Plaque Formation in a Mouse Model of Alzheimer's-like β-Amyloidosis.

Accumulation of amyloid-β peptide (Aβ) aggregates in synapses may contribute to the profound synaptic loss characteristic of Alzheimer's disease (AD). The origin of synaptic Aβ aggregates remains elusive, but loss of endosomal proteostasis may trigger their formation. In this study, we identified the synaptic compartments where Aβ accumulates, and performed a longitudinal analysis of synaptosomes isolated from brains of TgCRND8 APP transgenic mice of either sex. To evaluate the specific contribution of Aβ-degrading protease endothelin-converting enzyme (ECE-1) to synaptic/endosomal Aβ homeostasis, we analyzed the effect of partial Ece1 KO in brain and complete ECE1 KO in SH-SY5Y cells. Global inhibition of ECE family members was used to further assess their role in preventing synaptic Aβ accumulation. Results showed that, before extracellular amyloid deposition, synapses were burdened with detergent-soluble Aβ monomers, oligomers, and fibrils. Levels of all soluble Aβ species declined thereafter, as Aβ42 turned progressively insoluble and accumulated in Aβ-producing synaptic endosomal vesicles with characteristics of multivesicular bodies. Accordingly, fibrillar Aβ was detected in brain exosomes. ECE-1-deficient mice had significantly increased endogenous synaptosomal Aβ42 levels, and protease inhibitor experiments showed that, in TgCRND8 mice, synaptic Aβ42 became nearly resistant to degradation by ECE-related proteases. Our study supports that Aβ accumulating in synapses is produced locally, within endosomes, and does not require the presence of amyloid plaques. ECE-1 is a determinant factor controlling the accumulation and fibrillization of nascent Aβ in endosomes and, in TgCRND8 mice, Aβ overproduction causes rapid loss of Aβ42 solubility that curtails ECE-mediated degradation.SIGNIFICANCE STATEMENT Deposition of aggregated Aβ in extracellular plaques is a defining feature of AD. Aβ aggregates also accumulate in synapses and may contribute to the profound synaptic loss and cognitive dysfunction typical of the disease. However, it is not clear whether synaptotoxic Aβ is mainly derived from plaques or if it is produced and aggregated locally, within affected synaptic compartments. Filling this knowledge gap is important for the development of an effective treatment for AD, as extracellular and intrasynaptic pools of Aβ may not be equally modulated by immunotherapies or other therapeutic approaches. In this manuscript, we provide evidence that Aβ aggregates building up in synapses are formed locally, within synaptic endosomes, because of disruptions in nascent Aβ proteostasis.

Scanning Ion-Conductance Microscopy for Studying β-Amyloid Aggregate Formation on Living Cell Surfaces.

β-Amyloid aggregation on living cell surfaces is described as responsible for the neurotoxicity associated with different neurodegenerative diseases. It is suggested that the aggregation of β-amyloid (Aβ) peptide on neuronal cell surface leads to various deviations of its vital function due to myriad pathways defined by internalization of calcium ions, apoptosis promotion, reduction of membrane potential, synaptic activity loss, etc. These are associated with structural reorganizations and pathologies of the cell cytoskeleton mainly involving actin filaments and microtubules and consequently alterations of cell mechanical properties. The effect of amyloid oligomers on cells' Young's modulus has been observed in a variety of studies. However, the precise connection between the formation of amyloid aggregates on cell membranes and their effects on the local mechanical properties of living cells is still unresolved. In this work, we have used correlative scanning ion-conductance microscopy (SICM) to study cell topography, Young's modulus mapping, and confocal imaging of Aβ aggregate formation on living cell surfaces. However, it is well-known that the cytoskeleton state is highly connected to the intracellular level of reactive oxygen species (ROS). The effect of Aβ leads to the induction of oxidative stress, actin polymerization, and stress fiber formation. We measured the reactive oxygen species levels inside single cells using platinum nanoelectrodes to demonstrate the connection of ROS and Young's modulus of cells. SICM can be successfully applied to studying the cytotoxicity mechanisms of Aβ aggregates on living cell surfaces.