Aβ Peptide Research Articles

Amyloid beta 1-40 and 1-42 fibril ratios and maturation level cause conformational differences with minimal impact on autophagy and cytotoxicity.

The amyloid β (Aβ) peptide has a central role in Alzheimer's disease (AD) pathology. The peptide length can vary between 37 and 49 amino acids, with Aβ1-42 being considered the most disease-related length. However, Aβ1-40 is also found in Aβ plaques and has shown to form intertwined fibrils with Aβ1-42. The peptides have previously also shown to form different fibril conformations, proposed to be related to disease phenotype. To conduct more representative invitro experiments, it is vital to uncover the impact of different fibril conformations on neurons. Hence, we fibrillized different Aβ1-40:42 ratios in concentrations of 100:0, 90:10, 75:25, 50:50, 25:75, 10:90 and 0:100 for either 24 h (early fibrils) or 7 days (aged fibrils). These were then characterized based on fibril width, LCO-staining and antibody-staining. We further challenged differentiated neuronal-like SH-SY5Y human cells with the different fibrils and measured Aβ content, cytotoxicity and autophagy function at three different time-points: 3, 24, and 72 h. Our results revealed that both Aβ1-40:42 ratio and fibril maturation affect conformation of fibrils. We further show the impact of these conformation changes on the affinity to commonly used Aβ antibodies, primarily affecting Aβ1-40 rich aggregates. In addition, we demonstrate uptake of the aggregates by neuronally differentiated human cells, where aggregates with higher Aβ1-42 ratios generally caused higher cellular levels of Aβ. These differences in Aβ abundance did not cause changes in cytotoxicity nor in autophagy activation. Our results show the importance to consider conformational differences of Aβ fibrils, as this can have fundamental impact on Aβ antibody detection. Overall, these insights underline the need for further exploration of the impact of conformationally different fibrils and the need to reliably produce disease relevant Aβ aggregates.

Air pollution amyloidogenesis is attenuated by the gamma-secretase modulator GSM-15606.

Chronic air pollution (AirPoll) is associated with accelerated cognitive decline and risk of Alzheimer's disease (AD). Correspondingly, wild-type and AD-transgenic rodents exposed to AirPoll have increased amyloid peptides and behavioral impairments. We examined the γ-secretase modulator GSM-15606 for potential AirPoll protection by its attenuating of amyloid beta (Aβ)42 peptide production. Male and female wild-type mice were fed GSM-15606 during an 8-week inhalation exposure to AirPoll subfractions, ambient nanoparticulate matter (nPM), and diesel exhaust particles (DEP). GSM-15606 decreased Aβ42 during nPM and DEP exposure without changing beta- or gamma-secretase activity or BACE1 and PS1 protein levels. DEP increased lateral ventricle volume by 25%. These enzyme responses are relevant to AD drug treatments, as well as to the physiological functions of the Aβ42 peptide. GSM-15606 attenuation of Aβ42 may benefit human exposure to AirPoll. Gamma-secretase modulator (GSM-15606) attenuates the amyloidogenic amyloid beta (Aβ)42 peptide during exposure to air pollution, which may be a mechanism by which air pollution increases Alzheimer's disease (AD) risk. AD drug treatments may also consider Aβ homeostasis among the chronic effects of GSM-15606 and other amyloid reduction treatments on secretase enzymes.

Search for potential Alzheimer’s disease therapeutics: Identification of inhibitors of amyloid oligomerization with high affinity for the zinc-binding site

The progression of Aβ peptide aggregation in the brain has been suggested to play a significant role in the pathogenesis and development of Alzheimer’s disease. This study is intended to provide insight into the interactions between the zinc-binding site of beta-amyloids and the zinc ion itself. The absence of zinc bonded to the beta-amyloid has been shown to potentially slow down the progression of Alzheimer's disease, so the goal is to provide an analysis of available drugs that can be repurposed and could profoundly impact Alzheimer's disease treatment. We address how and with what strength the existing compounds bind with beta-amyloid, potentially replacing or blocking zinc and preventing it from attaching to the amyloid. The analysis was performed using molecular operating environment software, which, starting from a filtered database, identified the drugs most likely to bind to the zinc-binding site on beta-amyloid.

(Invited) Multiplexed CRISPR-Based ECL Assay for Alzheimer’s Biomarkers

Currently, more than 6 million Americans live with Alzheimer’s disease (AD), and it is projected to be 13 million by 2050. AD has no permanent cure yet, and early detection is important to slow down the progress of the disease. Diagnosis is complicated by AD’s similarity to other geriatric diseases. Beta-amyloid peptide (Aβ42), tau proteins and neurofilament light (NFL) measured in the cerebrospinal fluid (CSF) is a reasonably effective method for diagnostics, but very painful for the patients. MicroRNA’s (miRNAs) expressed in the brain are promising biomarkers and our goal of this study is to develop a sensitive and selective point-of-care (POC) test to detect AD specific miRNA (miRNA 30e, 34c and 200c) based on the CRISPR-Cas system. The Cas 13a protein has the regular sequence specific RNase activity followed by a collateral RNase activity. We used this feature of Cas 13a to generate an electrochemiluminescence (ECL) signal by binding specific miRNA biomarkers, and then collaterally cleaving poly-ribose guanine (poly-rG). This cleaved strands of poly-rG and rG itself are coreactants for ECL, and react with ECL polymer Ruthenium Polyvinyl Pyridine (RuPVP) to generate ECL. RuPVP is deposited into pyrolytic graphite (PG) micro wells. Using a 3D-printed microfluidic device equipped with the Pt reference and Ag/AgCl counter electrodes, patient serum mixed with poly-rG is introduced to the RuPVP coated electrode at 1.3 V to provide ECL light measured by a CCD camera. The assay was multiplexed to detect 3 AD specific miRNAs, and obtain a separate calibration for each miRNA biomarker with linear ranges from 70 pg/ mL to 7 µg/mL, from 7.4 pg/ mL to 74 µg/ mL and from 7.4 fg/ mL to 74 µg/ mL for 30e, 34c and 200c respectively. Preliminary LODs were 42 pg/ mL, 0.074 fg/ mL and 0.15 fg/ mL for miRNA 30e, 34c and 200c respectively. Results confirm the sensitivity of the assay. Further, spike recovery, cross reactivity studies and patient sample assays will be reported.

Novel Monoclonal Antibody Specific toward Amyloid-β Binds to a Unique Epitope within the N-Terminal Region.

Amyloid-β (Aβ) deposition throughout the neuroaxis is a classical hallmark of several neurodegenerative diseases, most notably Alzheimer's disease (AD). Aβ peptides of varied length and diverse structural conformations are deposited within the parenchyma and vasculature in the brains of individuals with AD. Neuropathologically, Aβ pathology can be assessed using antibodies to label and characterize their features, which in turn leads to a more extensive understanding of the pathological process. In the present study, we generated a novel monoclonal antibody, which we found to be specific for the N-terminal region of Aβ. This antibody reacted to amyloid precursor protein expressed in cultured cells and labels Aβ plaques and cerebral amyloid angiopathy in brain tissue from a mouse model of amyloidosis as well as post-mortem brain tissue from patients diagnosed with AD. This highly specific novel antibody will serve as a unique tool for future studies investigating Aβ deposition in novel mouse models and cross-sectional studies using post-mortem human tissue.

Manual and automatic assignment of two different Aβ40 amyloid fibril polymorphs using MAS solid-state NMR spectroscopy

Amyloid fibrils from Alzheimer’s amyloid-beta peptides (Aβ) are found to be polymorphic. So far, 14 Aβ40 fibril structures have been determined. The mechanism of why one particular protein sequence adopts so many different three-dimensional structures is yet not understood. In this work, we describe the assignment of the NMR chemical shifts of two Alzheimer’s disease fibril polymorphs, P1 and P2, which are formed by the amyloid-beta peptide Aβ40. The assignment is based on 13C-detected 3D NCACX and NCOCX experiments MAS solid-state NMR experiments. The fibril samples are prepared using an extensive seeding protocol in the absence and presence of the small heat shock protein αB-crystallin. In addition to manual assignments, we obtain chemical shift assignments using the automation software ARTINA. We present an analysis of the secondary chemical shifts and a discussion on the differences between the manual and automated assignment strategies.

An optimized UPLC-MS/MS method for human plasma amyloid-β 42 and 40 measurement and application in Alzheimer's disease diagnosis

Critical events in Alzheimer’s disease (AD) involve an imbalance between the production and clearance of amyloid-β (Aβ) peptides from the brain. The ratio of Aβ42 to Aβ40 in plasma was useful for evaluating AD, but quantification is limited by factors including preanalytical analyte loss and insufficient sensitivity. The availability of a targeted UPLC-MS/MS method with adequate analytical sensitivity and accurate values traceable to the SI units is essential for implementing a strategy for assay standardization. A targeted UPLC-MS/MS method for plasma Aβ42 and Aβ40 quantification was developed based on selected characteristic peptides spiked by 15N-labeled Aβ. The calibrator was assigned using an amino acid analysis reference method trace to SI units. UPLC-MS/MS conditions and sample preparation procedures were assessed. 59 plasma samples comparison were used to evaluate immunoassays. Additionally, two clinical cohorts were selected for diagnostic performance evaluation. The LOQ of Aβ42 and Aβ40 is 10 pg mL−1 and 20 pg mL−1, respectively. The linear range was 10–500 pg mL−1 for Aβ42 and 20–1000 pg mL−1 for Aβ40, recoveries between 95.3 % and 108.2 % for Aβ42, 93.2 % and 104.1 % for Aβ40, imprecisions were <7 %. The accuracy of method was validated by analysis of a certified reference material. Clinical cohorts for diagnostic performance evaluation shown that the area under the curve (AUC) for plasma Aβ42 and Aβ42/Aβ40 to differentiate between AD and CN were 0.767 and 0.799, respectively. A robust UPLC-MS/MS method was developed and demonstrated that suitable for a wide range of plasma Aβ42 and Aβ40. Applied to the investigation of clinically discrepant results, this method can act as an arbiter of the concentration of plasma Aβ42 and Aβ40 present.

Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute β-amyloid infusion model

Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer’s disease (AD) model by infusing Aβ into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.

Advancing Alzheimer’s biomarker Detection: A hairpin Aptamer-Based competitive electrochemical biosensor for trace Amyloid beta 40 analysis

Accurate detection of Alzheimer’s disease (AD) core biomarkers in body fluid is critical for identifying latent asymptomatic AD patients and prediction AD progress. Amyloid beta 1–40 (Aβ-40) as one of the core biomarkers, is expected to be an early diagnostic indicator for AD. Here, we establish a competitive method based on hairpin-structured aptamer for rapid and highly sensitive detection of Aβ-40 using square wave voltammetry (SWV). A hairpin aptamer with redox-active moiety methylene blue (MB) are immobilized on a gold working electrode as a recognition element. In the detection, a short complementary oligonucleotide strand is first introduced to switch on the hairpin, whereafter the targets Aβ-40 join in and selectively react with the aptamer in a competitive manner with the complementary strand, leading to the changes in the proximity of MB to the electrode and thereby in the electrochemical signal. Various parameters such as aptamer concentration, complementary chain length, incubation time, and temperature were optimized to achieve maximum sensing performance. By introducing a complementary chain, the sensor significantly reduces the detection limit to 7.14 pg/mL, with a dynamic range of 20 pg/mL to 200 ng/mL. Additionally, high selectivity of the sensor for Aβ-40 monomer (Aβ-40 m) over other forms of Aβ peptides has been validated. The hairpin-mediated detection method enables rapid, facile and highly sensitive detection of Aβ-40 using low-cost screen-printed electrode (SPE) platform, providing a wide range of possibilities for the early diagnosis of AD in point-of-care technologies (POCT).

Repurposing Anidulafungin for Alzheimer's Disease via Fragment-Based Drug Discovery.

The misfolding and aggregation of beta-amyloid (Aβ) peptides have been implicated as key pathogenic events in the early stages of Alzheimer's disease (AD). Inhibiting Aβ aggregation represents a potential disease-modifying therapeutic approach to AD treatment. Previous studies have identified various molecules that inhibit Aβ aggregation, some of which share common chemical substructures (fragments) that may be key to their inhibitory activity. Employing fragment-based drug discovery (FBDD) methods may facilitate the identification of these fragments, which can subsequently be used to screen new inhibitors and provide leads for further drug development. In this study, we used an in silico FBDD approach to identify 17 fragment clusters that are significantly enriched among Aβ aggregation inhibitors. These fragments were then used to screen anti-infective agents, a promising drug class for repurposing against amyloid aggregation. This screening process identified 16 anti-infective drugs, 5 of which were chosen for further investigation. Among the 5 candidates, anidulafungin, an antifungal compound, showed high efficacy in inhibiting Aβ aggregation in vitro. Kinetic analysis revealed that anidulafungin selectively blocks the primary nucleation step of Aβ aggregation, substantially delaying Aβ fibril formation. Cell viability assays demonstrated that anidulafungin can reduce the toxicity of oligomeric Aβ on BV2 microglia cells. Molecular docking simulations predicted that anidulafungin interacted with various Aβ species, including monomers, oligomers, and fibrils, potentially explaining its activity against Aβ aggregation and toxicity. This study suggests that anidulafungin is a potential drug to be repurposed for AD, and FBDD is a promising approach for discovering drugs to combat Aβ aggregation.

Edaravone N-benzyl pyridinium derivatives: BACE-1 inhibition, kinetics and in silico binding pose determination

BACE-1 plays a pivotal role in the production of β-amyloid (Aβ) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC50 = 44.10 µM - 123.70 µM) and obtained IC50 values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC50 = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC50 of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

Ru(II)-arene azole complexes as anti-amyloid-β agents.

With the recent clinical success of anti-amyloid-β (Aβ) monoclonal antibodies, there is a renewed interest in agents which target the Aβ peptide of Alzheimer's disease (AD). Metal complexes are particularly well-suited for this development, given their structural versatility and ability to form stabile interactions with soluble Aβ. In this report, a small series of ruthenium-arene complexes were evaluated for their respective ability to modulate both the aggregation and cytotoxicity of Aβ. First, the stability of the complexes was evaluated in a variety of aqueous media where the complexes demonstrated exceptional stability. Next, the ability to coordinate and modulate the Aβ peptide was evaluated using several spectroscopic methods, including thioflavin T (ThT) fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Overall, the complex RuBO consistently gave the greatest inhibitory action towards Aβ aggregation, which correlated with its ability to coordinate to Aβ in solution. Furthermore, RuBO also had the lowest affinity for serum albumin, which is a key consideration for a neurotherapeutic, as this protein does not cross the blood brain barrier. Lastly, RuBO also displayed promising neuroprotective properties, as it had the greatest inhibition of Aβ-inducted cytotoxicity.

Targeting the hydrophobic region of pyroglutamate-modified amyloid-β by tyrocidine A prevents its nucleation-aggregation process and its "catalytic effect" on the Aβsaggregation.

Pyroglutamate (pE)-modified amyloid-β (Aβ) peptides play a crucial role in the development of Alzheimer's disease. pEAβ3-42 can rapidly form oligomers that gradually elongate hydrophobic segments to form β-sheet-rich amyloid intermediates, ultimately resulting in the formation of mature amyloid fibrils. pEAβ3-42 can also catalyze the aggregation of Aβ species and subsequently accelerate the formation of amyloid senile plaques. Considering the recent clinical success of the pEAβ3-42-targeting antibody donanemab, molecules that strongly bind pEAβ3-42 and prevent its aggregation and catalytic effect on Aβs may also provide potential therapeutic options for Alzheimer's disease. Here, we demonstrate that the natural antibiotic cyclopeptide tyrocidine A (TA) not only strongly inhibits the aggregation of Aβ1-42 as previously reported, but also interacts with the hydrophobic C-terminus and middle domain of pEAβ3-42 to maintain an unordered conformation, effectively impeding the formation of initial oligomers and subsequently halting the aggregation of pEAβ3-42. Furthermore, TA can disrupt the "catalytic effect" of pEAβ3-42 on amyloid aggregates, effectively suppressing Aβaggregation and ultimately preventing the pathological events induced by Aβs.

Cerebrovascular Endothelial Dysfunction: Role of BACE1.

Dysfunctional endothelium is increasingly recognized as a mechanistic link between cardiovascular risk factors and dementia, including Alzheimer disease. BACE1 (β-site amyloid-β precursor protein-cleaving enzyme 1) is responsible for β-processing of APP (amyloid-β precursor protein), the first step in the production of Aβ (amyloid-β) peptides, major culprits in the pathogenesis of Alzheimer disease. Under pathological conditions, excessive activation of BACE1 exerts detrimental effects on endothelial function by Aβ-dependent and Aβ-independent mechanisms. High local concentration of Aβ in the brain blood vessels is responsible for the loss of key vascular protective functions of endothelial cells. More recent studies recognized significant contribution of Aβ-independent proteolytic activity of endothelial BACE1 to the pathogenesis of endothelial dysfunction. This review critically evaluates existing evidence supporting the concept that excessive activation of BACE1 expressed in the cerebrovascular endothelium impairs key homeostatic functions of the brain blood vessels. This concept has important therapeutic implications. Indeed, improved understanding of the mechanisms of endothelial dysfunction may help in efforts to develop new approaches to the protection and preservation of healthy cerebrovascular function.

Neuroprotective Potential of Photobiomodulation Therapy: Mitigating Amyloid-Beta Accumulation and Modulating Acetylcholine Levels in an In Vitro Model of Alzheimer's Disease.

Objective: To investigate the effects of photobiomodulation therapy (PBMT) at 660 and 810 nm on amyloid-beta (Aβ)42-induced toxicity in differentiated SH-SY5Y cells and to assess its impact on Aβ42 accumulation and cholinergic neurotransmission. Background: Alzheimer's disease (AD) is characterized by the accumulation of Aβ peptides, leading to neurodegeneration, cholinergic deficit, and cognitive decline. PBMT has emerged as a potential therapeutic approach to mitigate Aβ-induced toxicity and enhance cholinergic function. Methods: Differentiated neurons were treated with 1 μM Aβ42 for 1 day, followed by daily PBMT at wavelengths of 660 and 810 nm for 7 days. Treatments used LEDs emitting continuous wave light at a power density of 5 mW/cm2 for 10 min daily to achieve an energy density of 3 J/cm2. Results: Differentiated SH-SY5Y cells exhibited increased Aβ42 aggregation, neurite retraction, and reduced cell viability. PBMT at 810 nm significantly mitigated the Aβ42-induced toxicity in these cells, as evidenced by reduced Aβ42 aggregation, neurite retraction, and improved cell viability and neuronal morphology. Notably, this treatment also restored acetylcholine levels in the neurons exposed to Aβ42. Conclusions: PBMT at 810 nm effectively reduces Aβ42-induced toxicity and supports neuronal survival, highlighting its neuroprotective effects on cholinergic neurons. By shedding light on the impact of low-level light therapy on Aβ42 accumulation and cellular processes. These findings advocate for further research to elucidate the mechanisms of PBMT and validate its clinical relevance in AD management.

Role of short chain fatty acids on astrocytes and microglia in Alzheimer's disease brain

SummaryShort‐chain fatty acids (SCFAs) hold exert many nutritional benefits on both physiological and pathological processes, including host metabolism, immune modulation, and appetite control. Originating from the microbial fermentation of resistant starches and dietary fibre in the colon, SCFAs have the capability to traverse the blood–brain barrier (BBB). It is evident that SCFAs play a critical role in the development of neurodegenerative disorders such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised by the deposition of amyloid β peptides (Aβ) and tau hyperphosphorylation. SCFAs have demonstrated the potential to interfere with the protein–protein interactions required for Aβ peptides to form neurotoxic oligomers. Moreover, research indicates that the SCFAs ability to maintain endothelial integrity and interact with neuroglial cells through the BBB may assist in downregulating excessive neuroinflammatory responses to amyloid peptides. This review summarises the research on SCFAs' potential role in AD and understand their mechanism of actions on astrocytes and microglia.

Aggregation Dynamics of a 150 kDa Aβ42 Oligomer: Insights from Cryo Electron Microscopy and Multimodal Analysis.

I.Protein misfolding is a widespread phenomenon that can result in the formation of protein aggregates, which are markers of various disease states, including Alzheimer's disease (AD). In AD, amyloid beta (Aβ) peptides, particularly Aβ40 and Aβ42, are key players in the disease's progression, as they aggregate to form amyloid plaques and contribute to neuronal toxicity. Recent research has shifted attention from solely Aβ fibrils to also include Aβ protofibrils and oligomers as potentially critical pathogenic agents. Particularly, oligomers demonstrate greater toxicity compared to other Aβ specie. Hence, there is an increased interest in studying the correlation between toxicity and their structure and aggregation pathway. The present study investigates the aggregation of a 150 kDa Aβ42 oligomer that does not lead to fibril formation over time. Using negative stain transmission electron microscopy (TEM), size exclusion chromatography (SEC), dynamic light scattering (DLS), and cryo-electron microscopy (cryo-EM), we demonstrate that 150 kDa Aβ42 oligomers form higher-order string-like assemblies over time. The strings are unique from the classical Aβ fibril structures. The significance of our work lies in elucidating molecular behavior of a novel non-fibrillar form of Aβ42 aggregate.

Proteomic Analysis Reveals Physiological Activities of Aβ Peptide for Alzheimer's Disease.

With the rapid progress in deciphering the pathogenesis of Alzheimer's disease (AD), it has been widely accepted that the accumulation of misfolded amyloid β (Aβ) in the brain could cause the neurodegeneration in AD. Although much evidence demonstrates the neurotoxicity of Aβ, the role of Aβ in the nervous system are complex. However, more comprehensive studies are needed to understand the physiological effect of Aβ40 monomers in depth. To explore the physiological mechanism of Aβ, we employed mass spectrometry to investigate the altered proteomic events induced by a lower submicromolar concentration of Aβ. Human neuroblastoma SH-SY5Y cells were exposed to five different concentrations of Aβ1-40 monomers and collected at four time points. The proteomic analysis revealed the time-course behavior of proteins involved in biological processes, such as RNA splicing, nuclear transport and protein localization. Further biological studies indicated that Aβ40 monomers may activate PI3K/AKT signaling to regulate p-Tau, Ezrin and MAP2. These three proteins are associated with dendritic morphogenesis, neuronal polarity, synaptogenesis, axon establishment and axon elongation. Moreover, Aβ40 monomers may regulate their physiological forms by inhibiting the expression of BACE1 and APP via activation of the ERK1/2 pathway. A comprehensive exploration of pathological and physiological mechanisms of Aβ is beneficial for exploring novel treatment.

Investigation of the Aggregation of Aβ Peptide (1-40) in the Presence of κ-Carrageenan-Stabilised Liposomes Loaded with Homotaurine.

The kinetics of amyloid aggregation was studied indirectly by monitoring the changes in the polydispersity of mixed dispersion of amyloid β peptide (1-40) and composite liposomes. The liposomes were prepared from the 1,2-dioleoyl-sn-glicero-3-phoshocholine (DOPC) phospholipid and stabilised by the electrostatic adsorption of κ-carrageenan. The produced homotaurine-loaded and unloaded liposomes had a highly negative electrokinetic potential and remarkable stability in phosphate buffer (pH 4 and 7.4). For the first time, the appearance and evolution of the aggregation of Aβ were presented through the variation in the standard percentile readings (D10, D50, and D90) obtained from the particle size distribution analysis. The kinetic experiments indicated the appearance of the first aggregates almost 30 min after mixing the liposomes and peptide solution. It was observed that by adding unloaded liposomes, the size of 90% of the particles in the dispersion (D90) increased. In contrast, the addition of homotaurine-loaded liposomes had almost minimal impact on the size of the fractions of larger particles during the kinetic experiments. Despite the specific bioactivity of homotaurine in the presence of natural cell membranes, this study reported an additional inhibitory effect of the compound on the amyloid peptide aggregation due to the charge effects and 'molecular crowding'.

Exploring the complexity of amyloid-beta fibrils: structural polymorphisms and molecular interactions.

The aggregation of amyloid-beta (Aβ) peptides into cross-β structures forms a variety of distinct fibril conformations, potentially correlating with variations in neurodegenerative disease progression. Recent advances in techniques such as X-ray crystallography, solid-state NMR, and cryo-electron microscopy have enabled the development of high-resolution molecular structures of these polymorphic amyloid fibrils, which are either grown in vitro or isolated from human and transgenic mouse brain tissues. This article reviews our current understanding of the structural polymorphisms in amyloid fibrils formed by Aβ40 and Aβ42, as well as disease-associated mutants of Aβ peptides. The aim is to enhance our understanding of various molecular interactions, including hydrophobic and ionic interactions, within and among cross-β structures.