Amyloid Peptide Aβ Research Articles

Tau Protein and Tauopathies: Exploring Tau Protein-Protein and Microtubule Interactions, Cross-Interactions and Therapeutic Strategies.

Tau, a microtubule-associated protein (MAP), is essential to maintaining neuronal stability and function in the healthy brain. However, aberrant modifications and pathological aggregations of Tau are implicated in various neurodegenerative disorders, collectively known as tauopathies. The most common Tauopathy is Alzheimer's Disease (AD) counting nowadays more than 60 million patients worldwide. This comprehensive review delves into the multifaceted realm of Tau protein, puzzling out its intricate involvement in both physiological and pathological roles. Emphasis is put on Tau Protein-Protein Interactions (PPIs), depicting its interaction with tubulin, microtubules and its cross-interaction with other proteins such as Aβ1-42, α-synuclein, and the chaperone machinery. In the realm of therapeutic strategies, an overview of diverse possibilities is presented with their relative clinical progresses. The focus is mostly addressed to Tau protein aggregation inhibitors including recent small molecules, short peptides and peptidomimetics with specific focus on compounds that showed a double anti aggregative activity on both Tau protein and Aβ amyloid peptide. This review amalgamates current knowledge on Tau protein and evolving therapeutic strategies, providing a comprehensive resource for researchers seeking to deepen their understanding of the Tau protein and for scientists involved in the development of new peptide-based anti-aggregative Tau compounds.

Capture enhanced neutron irradiation for the treatment of the Alzheimer Disease: Micro-nanodosimetric characterization of beta amyloid peptide samples

Alzheimer Disease (AD) is the most common cause of dementia. 46.8 million people live with AD worldwide, with numbers projected to almost double every 20 years. The etiological mechanisms underlying the neuropathological changes in AD remain unclear. The beta amyloid peptide Aβ is considered to be the main culprit of the pathological processes. NECTAR (NEutron Capture-enhanced Treatment of neurotoxic Amyloid aggRegates) project proposes an alternative and revolutionary strategy to address AD, investigating the safety, feasibility and effectiveness of a Capture-Enhanced Neutron Irradiation to structurally damage Aβ aggregates, by exploiting capture agent vectors containing B-10 and Gd-157.Among many others, one of the goals of the project is to perform calculations and measurements of microdosimetric and nanodosimetric quantities to characterize the effect of reaction products at local level and to link it to the fibrils depolymerization process. In this framework, a new low-pressure tissue-equivalent proportional counter (TEPC) was designed and developed. The system is a wall-free TEPC able to measure micro-nanometric dose deposition for different biological samples. It is characterized by two main features: i) a wall-less structure allows the charged particles produced by the sample to access the sensitive volume, where their effects are studied; ii) a trigger system enables the assessment of the number of ionizations induced in the sensitive volume related to a single primary particle for obtaining nandosimetric information.The prototype system was tested in the PGNAA (Prompt Gamma Neutron Activation Analysis) facility of the LENA reactor (Pavia) to directly study secondary particles from Aβ fibrils, loaded with Boron. Results of the micro-nanodosimetric characterization of high LET secondaries from Aβ-fibrils were compared to a reference Boron sample. For a 500 nm simulated site size, the presence of Boron in the Aβ sample greatly populates microdosimetric spectra at high lineal energy values. Instead, lower LET particles (photons, protons) from reactions on the other Aβ aggregate solution molecules populate the low lineal energy portion of the distribution.The nanodosimetric distributions highlights the presence of different field components on the nanodosimetric spectra: low LET particles (protons/electrons) produce small ionization clusters, while alpha and Lithium ions induce larger clusters, thus have a higher biological effect. The nanodosimetric measurements have been compared with Monte Carlo simulations performed with a track-structure code, showing a good agreement.This multi-level approach provides a deeper physical understanding of the mixed secondaries field coming from B-enriched target, as well as a reference for the biological effect on Aβ fibrils at nanometer level. These preliminary measurements represent the first microdosimetric and nanodosimetric characterization of the secondary mixed field directly emitted by a biological sample irradiated with neutrons.

The Influence of Lipid Electric Charge on the Binding of Aβ(1-42) Amyloid Peptide to Bilayers in the Liquid-Ordered State.

The amyloidogenic Aβ peptides are widely considered as a pathogenic agent in Alzheimer's disease. Aβ(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aβ(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aβ(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aβ(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aβ(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides.

Structure Comparison of Beta Amyloid Peptide Aβ 1-42 Isoforms. Molecular Dynamics Modeling.

Beta amyloid peptide Aβ 1-42 (Aβ42) has a unique dual role in the human organism, as both the peptide with an important physiological function and one of the most toxic biological compounds provoking Alzheimer's disease (AD). There are several known Aβ42 isoforms that we discuss here that are highly neurotoxic and lead to the early onset of AD. Aβ42 is an intrinsically disordered protein with no experimentally solved structure under physiological conditions. The objective of this research was to establish the appropriate molecular dynamics (MD) methodology and model a uniform set of structures for the Aβ42 isoforms that form the core of this study. For that purpose, force field selection and verification including convergence testing for MD simulations was made. Replica exchange MD and conventional MD modeling of several Aβ42 and Aβ16 isoforms that have neurotoxic and amyloidogenic effects impacting the severity of Alzheimer's disease were carried out with the optimal force field and solvent parameters. A standardized ensemble of structures for the Aβ42 and Aβ16 isoforms covering 30-50% of the conformational ensembles extracted from the free energy minima was calculated from MD trajectories. The resulting data set of modeled structures includes Aβ42 wild type, isoD7, pS8, D7H, and H6R-Aβ42 and Aβ16 wild type, isoD7, pS8, D7H, and H6R-Aβ16. The representative structures are given in the Supporting Information; they are open for public access. In the study, we also evaluated the differences between the structures of Aβ42 isoforms and speculate on their possible relevance to the known functions. Utilizing several representative structures for a single disordered protein for docking, with their subsequent averaging by conformations, would markedly increase the reliability of docking results.

Tryptophan Metabolism in Alzheimer's Disease with the Involvement of Microglia and Astrocyte Crosstalk and Gut-Brain Axis.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by extracellular Amyloid Aβ peptide (Aβ) deposition and intracellular Tau protein aggregation. Glia, especially microglia and astrocytes are core participants during the progression of AD and these cells are the mediators of Aβ clearance and degradation. The microbiota-gut-brain axis (MGBA) is a complex interactive network between the gut and brain involved in neurodegeneration. MGBA affects the function of glia in the central nervous system (CNS), and microbial metabolites regulate the communication between astrocytes and microglia; however, whether such communication is part of AD pathophysiology remains unknown. One of the potential links in bilateral gut-brain communication is tryptophan (Trp) metabolism. The microbiota-originated Trp and its metabolites enter the CNS to control microglial activation, and the activated microglia subsequently affect astrocyte functions. The present review highlights the role of MGBA in AD pathology, especially the roles of Trp per se and its metabolism as a part of the gut microbiota and brain communications. We (i) discuss the roles of Trp derivatives in microglia-astrocyte crosstalk from a bioinformatics perspective, (ii) describe the role of glia polarization in the microglia-astrocyte crosstalk and AD pathology, and (iii) summarize the potential of Trp metabolism as a therapeutic target. Finally, we review the role of Trp in AD from the perspective of the gut-brain axis and microglia, as well as astrocyte crosstalk, to inspire the discovery of novel AD therapeutics.

Interfacial Aβ fibril formation is modulated by the disorder-order state of the lipids: The concept of the physical environment as amyloid inductor in biomembranes

The behavior of amphiphilic molecules such as lipids, peptides and their mixtures at the air/water interface allow us to evaluate and visualize the arrangement formed in a confined and controlled surface area. We have studied the surface properties of the zwitterionic DPPC lipid and Aβ(1–40) amyloid peptide in mixed films at different temperatures (from 15 to 40 °C). In this range of temperature the surface properties of pure Aβ(1–40) peptide remained unchanged, whereas DPPC undergoes its characteristic liquid-expanded → liquid-condensed bidimensional phase transition that depends on the temperature and lateral pressure. This particular property of DPPC makes it possible to dynamically study the influence of the lipid phase state on amyloid structure formation at the interface in a continuous, isothermal and abrupt change on the environmental condition. As the mixed film is compressed the fibril-like structure of Aβ(1–40) is triggered specifically in the liquid-expanded region, independently of temperature, and it is selectively excluded from the well-visible liquid condensed domains of DPPC. The Aβ amyloid fibers were visualized by using BAM and AFM and they were Thio T positive. In mixed DPPC/Aβ(1–40) films the condensed domains (in between 11 mN/m to 20 mN/m) become irregular probably due to the fibril-like structures is imposing additional lateral stress sequestering lipid molecules in the surrounding liquid-expanded phase to self-organize into amyloids.

An activatable small-molecule fluorogenic probe for detection and quantification of beta-amyloid aggregates

Extracellular accumulation of β amyloid (Aβ) peptides in the brain is thought to be a pathological hallmark and initial event before the symptom starts of Alzheimer’s patients. Herein, we developed two series of benzo[d]thiazole-based small-molecule compounds (BM1-BM4, BPM1-BPM4) with a donor–acceptor (D-A) or donor-π-acceptor (D-π-A) architecture, respectively, based on structure–activity relationship. Among them, the optimized BPM1 not only displayed the highest binding affinity to Aβ aggregates over other proteins or Aβ monomers, but was readily activated its fluorescence with 10-fold fluorescence enhancement, allowing for specifically and sensitively detecting Aβ aggregates. BPM1 also exhibits several other advantages including low molecular weight, low cytotoxicity and excellent biological stability. Besides, cell staining results confirmed that SK-N-BE(2) cells can be fluorescently lighted up as well as cell permeability and damage when treated with BPM1-bound Aβ1-42 aggregates.

Disrupting Dimeric β-Amyloid by Electric Fields.

The early oligomers of the amyloid Aβ peptide are implicated in Alzheimer's disease, but their transient nature complicates the characterization of their structure and toxicity. Here, we investigate the stability of the minimal toxic species, i.e., β-amyloid dimers, in the presence of an oscillating electric field. We first use deep learning (AlphaFold-multimer) for generating initial models of Aβ42 dimers. The flexibility and secondary structure content of the models are then analyzed by multiple runs of molecular dynamics (MD). Structurally stable models are similar to ensemble representatives from microsecond-long MD sampling. Finally, we employ the validated model as the starting structure of MD simulations in the presence of an external oscillating electric field and observe a fast decay of β-sheet content at high field strengths. Control simulations using the helical dimer of the 42-residue leucine zipper peptide show higher structural stability than the Aβ42 dimer. The simulation results provide evidence that an external electric field (oscillating at 1 GHz) can disrupt amyloid oligomers which should be further investigated by experiments with brain organoids in vitro and eventually in vivo.

Molecular mechanisms and genetics of Alzheimer’s disease

Abstract Dementia is mostly caused by neurodegenerative diseases like Alzheimer’s disease (AD). AD is the most common form of dementia. It is caused by both genetic and environmental factors. Due to neuronal death in a number of brain regions, including the hippocampus, entorhinal areas, temporal lobe, and cingulate cortex, AD causes memory loss and gradual cognitive impairment. The condition’s two main pathogenic components are intracellular neurofibrillary tangles created by clusters of hyperphosphorylated tau protein and amyloid plaques made up of extracellular amyloid (Aβ) peptide aggregates. In contrast to the APOE- ε4 allele, which was found to have a significant impact on late-onset AD, presenilin 1, presenilin 2, amyloid precursor protein were genetic risk factors that were causal for early-onset AD. Misfolded proteins accumulate within the neuron, causing prolonged cellular stress in AD, a progressive neurodegenerative disease. Neurofibrillary tangles and senile plaques are two of the neuropathological hallmarks of Alzheimer’s disease that lead to the destruction of synapses and the death of neurons. AD is mostly caused by the death of nerves, particularly cholinergic nerves. In the absence of these cholinergic neurons, acetylcholine levels fall. This review discusses key genes involved in the pathogenesis and pathophysiology of AD, as well as the disease’s molecular mechanisms.

Role of oxidative stress in Alzheimer's disease

Alzheimer's disease is the leading cause of disability in people over 65. Amyloid (Aβ) peptide deposition, neurofibrillary tangles of hyperphosphorylated protein, and dementia are hallmarks of AD [1]. The neurotoxic oligomer Aβ peptide and tau protein [2] mediate neurodegeneration, one of the main causes of the disease. Oxidative stress [3], an imbalance between antioxidants and oxidants, causes and exacerbates these symptoms. Free radicals, which have one or more unpaired electrons in their outer shell, can augment or reduce antioxidant defence, causing this imbalance. The reduction of molecular oxygen in water produces superoxide, which produces hydrogen peroxide by adding an electron. Reactive oxygen species (ROS) [4]—hydroxyl radicals produced by hydrogen peroxide reduction—can react with lipids, proteins, nucleic acids, and other molecules and change their structures and activities. Due to its makeup, ROS affects tissues and organs, particularly the sensitive brain. High oxygen usage and highly oxidizable lipids make up the brain.

Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer's Disease.

Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer's disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aβ) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD.

DNA Aβ42 immunization via needle-less Jet injection in mice and rabbits as potential immunotherapy for Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia found in the elderly and disease progression is associated with accumulation of Amyloid beta 1–42 (Aβ42) in brain. An immune-mediated approach as a preventive intervention to reduce amyloid plaques without causing brain inflammation is highly desirable for future clinical use. Genetic immunization, in which the immunizing agent is DNA encoding Aβ42, has great potential because the immune response to DNA delivered into the skin is generally non-inflammatory, and thus differs quantitatively and qualitatively from immune responses elicited by peptides, which are inflammatory with production of IFNγ and IL-17 cytokines by activated T cells. DNA immunization has historically been proven difficult to apply to larger mammals. A potential barrier to use DNA immunization in large mammals is the method for delivery of the DNA antigen. We tested jet injection in mice and rabbits and found good antibody production and safe immune responses (no inflammatory cytokines). We found significant reduction of amyloid plaques and Aβ peptides in brains of the DNA Aβ42 immunized 3xTg-AD mouse model. This study was designed to optimize DNA delivery for possible testing of the DNA Aβ42 vaccine for AD prevention in a clinical trial.

Neuronal deletion of nSMase2 reduces the production of Aβ and directly protects neurons

Extracellular vesicles (EVs) have been proposed to regulate the deposition of Aβ. Multiple publications have shown that APP, amyloid processing enzymes and Aβ peptides are associated with EVs. However, very little Aβ is associated with EVs compared with the total amount Aβ present in human plasma, CSF, or supernatants from cultured neurons. The involvement of EVs has largely been inferred by pharmacological inhibition or whole body deletion of the sphingomyelin hydrolase neutral sphingomyelinase-2 (nSMase2) that is a key regulator for the biogenesis of at-least one population of EVs. Here we used a Cre-Lox system to selectively delete nSMase2 from pyramidal neurons in APP/PS1 mice (APP/PS1-SMPD3-Nex1) and found a ∼ 70% reduction in Aβ deposition at 6 months of age and ∼ 35% reduction at 12 months of age in both cortex and hippocampus. Brain ceramides were increased in APP/PS1 compared with Wt mice, but were similar to Wt in APP/PS1-SMPD3-Nex1 mice suggesting that elevated brain ceramides in this model involves neuronally expressed nSMase2. Reduced levels of PSD95 and deficits of long-term potentiation in APP/PS1 mice were normalized in APP/PS1-SMPD3-Nex1 mice. In contrast, elevated levels of IL-1β, IL-8 and TNFα in APP/PS1 mice were not normalized in APP/PS1-SMPD3-Nex1 mice compared with APP/PS1 mice. Mechanistic studies showed that the size of liquid ordered membrane microdomains was increased in APP/PS1 mice, as were the amounts of APP and BACE1 localized to these microdomains. Pharmacological inhibition of nSMase2 activity with PDDC reduced the size of the liquid ordered membrane microdomains, reduced the localization of APP with BACE1 and reduced the production of Aβ1–40 and Aβ1–42. Although inhibition of nSMase2 reduced the release and increased the size of EVs, very little Aβ was associated with EVs in all conditions tested. We also found that nSMase2 directly protected neurons from the toxic effects of oligomerized Aβ and preserved neural network connectivity despite considerable Aβ deposition. These data demonstrate that nSMase2 plays a role in the production of Aβ by stabilizing the interaction of APP with BACE1 in liquid ordered membrane microdomains, and directly protects neurons from the toxic effects of Aβ. The effects of inhibiting nSMase2 on EV biogenesis may be independent from effects on Aβ production and neuronal protection.

Taylor dispersion analysis discloses the impairment of Aβ peptide aggregation by the presence of a fluorescent tag.

The use of fluorescently tagged amyloid peptides, implicated in Alzheimer's disease, to study their aggregation at low concentrations is a common method; however, the fluorescent tag should not introduce a bias in the aggregation process. In this work, native amyloid peptides Aβ(1-40) and Aβ(1-42) and fluorescein-5-isothiocyanate (FITC), tagged ones, were studied using Taylor dispersion analysis coupled with a simultaneous UV and light-emitting diode-induced fluorescence detection, to unravel the effect of FITC on the aggregation process. For that, a total concentration of 100µM of peptides consisting of a mixture of native and tagged ones (up to 10% in moles) was applied. Results demonstrated that FITC had a strong inhibition effect upon the aggregation behaviour of Aβ(1-42), whereas for Aβ(1-40), only a retardation in kinetics was observed. It was also shown that when mixed solutions of Aβ(1-40) and Aβ(1-42) are used, the Aβ(1-42) alloform was the leading peptide in the aggregation process, and when the latter was tagged, the aggregation kinetics decreased but the lifetime of potentially toxic oligomers was drastically increased. These results confirmed that the hydrophilicity of the N-terminus part of the peptide plays a major role in the aggregation process.

Proteomics Evidence of the Role of TDMQ20 in the Cholinergic System and Synaptic Transmission in a Mouse Model of Alzheimer's Disease.

The interaction between copper ions and amyloid peptide Aβ has been reported to be involved in Alzheimer's disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aβ complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aβ1-16 complex and restore cognitive and behavioral deficits in AD mouse models. For a better understanding of the mechanism of action of TDMQ20, we decided to investigate the change of profile of proteins expressed in 5xFAD mice after an oral treatment of TDMQ20 (dose = 10 mg/kg, once every two days for 3 months, in total 45 times). Clioquinol (CQ), a non-specific chelator, has been used as a comparator. Here, we report the proteomic alterations in the cortex of 5xFAD mice using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. The results indicated that 178 differentially expressed proteins (DEPs) have been identified in the AD mouse group with respect to wild type (WT) animals (AD/WT). After treatment by TDMQ20, 35 DEPs were found common in AD/WT and TDMQ20/AD groups in an opposite change manner (up- or down-regulated, respectively). In addition, among the 35 DEPs mentioned above, 10 common target proteins have been identified in AD/WT, TDMQ20/AD, and CQ/AD groups, among which 3 target proteins were successfully validated by western blot analysis. In particular, the expression levels of ChAT and CHRM4 are significantly increased upon TDMQ20 treatment with respect to 5xFAD mice, while CQ did not significantly change the expression of these proteins. Our study suggests the involvement of the copper chelator TDMQ20 on the cholinergic system, a feature that may explain the improved cognitive and behavioral performance in AD mice upon oral treatment of TDMQ20.

Multi-Target Mechanisms of Phytochemicals in Alzheimer's Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a tangle-shaped accumulation of beta-amyloid peptide fragments and Tau protein in brain neurons. The pathophysiological mechanism involves the presence of Aβ-amyloid peptide, Tau protein, oxidative stress, and an exacerbated neuro-inflammatory response. This review aims to offer an updated compendium of the most recent and promising advances in AD treatment through the administration of phytochemicals. The literature survey was carried out by electronic search in the following specialized databases PubMed/Medline, Embase, TRIP database, Google Scholar, Wiley, and Web of Science regarding published works that included molecular mechanisms and signaling pathways targeted by phytochemicals in various experimental models of Alzheimer’s disease in vitro and in vivo. The results of the studies showed that the use of phytochemicals against AD has gained relevance due to their antioxidant, anti-neuroinflammatory, anti-amyloid, and anti-hyperphosphorylation properties of Tau protein. Some bioactive compounds from plants have been shown to have the ability to prevent and stop the progression of Alzheimer’s.

Iron oxide nanoparticles-loaded hyaluronic acid nanogels for MRI-aided Alzheimer's disease theranostics

Despite eye-opening advances in developing novel therapeutics for hard-to-treat diseases, treatment of Alzheimer's disease (AD) is still known as the challenge of generations. By the way, scrutinizing and shedding light on a major cause of AD, i.e., fibrillation of β amyloid (Aβ) peptides, have paved the way to find an effective therapy for this life-threatening disease in the foreseeable future. In this study, we endeavored to push forward with research on AD therapy, even as much as an inch, by fabricating and evaluating a theranostic system based on iron oxide nanoparticles-loaded hyaluronic acid nanogels (Fe 3 O 4 -HyA NGs). Fe 3 O 4 nanoparticles were fabricated via a facile co-precipitation method and were loaded in HyA NGs in situ by formation of NGs using a thiolated HyA (HyA-SH) precursor. Standard structural analysis was performed on Fe 3 O 4 -HyA NGs, and the results revealed the NGs were negatively charged, which led to relatively poor adsorption of plasma proteins, and sized at the range of 120–150 nm. Also, Fe 3 O 4 -HyA NGs showed a superparamagnetic property with a magnetic saturation of about 62.8 emu/g indicating the successful loading of Fe 3 O 4 nanoparticles. Besides, findings of the cytotoxicity analysis could primarily show the NGs did not pose a noticeable risk to normal astrocyte cells (i.e., 96.7% cell viability at 100 µg/ml after 48 h treatment). Moreover, in vitro magnetic resonance imaging (MRI) analysis could reveal the noticeable potential ability of the Fe 3 O 4 -HyA NGs to generate negative contrast by reducing both T2-weighted and T2*-weighted MR signal intensities with a relaxation rate (r 2 ) of about 120.87 (1/mM.sec). Finally, Fe 3 O 4 -HyA NGs exhibited a potential ability to impede Aβ aggregation by around 44% at 10 µM; also, they could induce disaggregation of Aβ fibrils by about 13% at 10 µM. Hence, Fe 3 O 4 -HyA NGs could be a promising choice for AD theranostics and could be further scrutinized in vitro and in vivo .

Impact of Non-pharmacological Chronic Hypertension on a Transgenic Rat Model of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA), a common comorbidity of Alzheimer’s disease (AD), is a cerebral small vessel disease (CSVD) characterized by deposition of fibrillar amyloid β (Aβ) in blood vessels of the brain and promotes neuroinflammation and vascular cognitive impairment and dementia (VCID). Hypertension, a prominent non-amyloidal CSVD, has been found to increase risk of dementia, but clinical data regarding its effects in CAA patients is controversial. To understand the effects of hypertension on CAA, we bred rTg-DI transgenic rats, a model of CAA, with spontaneously hypertensive, stroke prone (SHR-SP) rats producing bigenic rTg-DI/SHR-SP and non-transgenic SHR-SP littermates. At 7 months (M) of age, cohorts of both rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic blood pressures. However, transgene human amyloid β-protein (Aβ) precursor and Aβ peptide levels, as well as behavioral testing showed no changes between bigenic rTg-DI/SHR-SP and rTg-DI rats. Subsequent cohorts of rats were aged further to 10 M where bigenic rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic and diastolic blood pressures. Vascular amyloid load in hippocampus and thalamus was significantly decreased, whereas pial surface vessel amyloid increased, in bigenic rTg-DI/SHR-SP rats compared to rTg-DI rats suggesting a redistribution of vascular amyloid in bigenic animals. There was activation of both astrocytes and microglia in rTg-DI rats and bigenic rTg-DI/SHR-SP rats not observed in SHR-SP rats indicating that glial activation was likely in response to the presence of vascular amyloid. Thalamic microbleeds were present in both rTg-DI rats and bigenic rTg-DI/SHR-SP rats. Although the number of thalamic small vessel occlusions were not different between rTg-DI and bigenic rTg-DI/SHR-SP rats, a significant difference in occlusion size and distribution in the thalamus was found. Proteomic analysis of cortical tissue indicated that bigenic rTg-DI/SHR-SP rats largely adopt features of the rTg-DI rats with enhancement of certain changes. Our findings indicate that at 10 M of age non-pharmacological hypertension in rTg-DI rats causes a redistribution of vascular amyloid and significantly alters the size and distribution of thalamic occluded vessels. In addition, our findings indicate that bigenic rTg-DI/SHR-SP rats provide a non-pharmacological model to further study hypertension and CAA as co-morbidities for CSVD and VCID.

Taylor Dispersion Analysis and Atomic Force Microscopy Provide a Quantitative Insight into the Aggregation Kinetics of Aβ (1-40)/Aβ (1-42) Amyloid Peptide Mixtures.

Aggregation of amyloid β peptides is known to be one of the main processes responsible for Alzheimer's disease. The resulting dementia is believed to be due in part to the formation of potentially toxic oligomers. However, the study of such intermediates and the understanding of how they form are very challenging because they are heterogeneous and transient in nature. Unfortunately, few techniques can quantify, in real time, the proportion and the size of the different soluble species during the aggregation process. In a previous work (Deleanu et al. Anal. Chem. 2021, 93, 6523-6533), we showed the potential of Taylor dispersion analysis (TDA) in amyloid speciation during the aggregation process of Aβ (1-40) and Aβ (1-42). The current work aims at exploring in detail the aggregation of amyloid Aβ (1-40):Aβ (1-42) peptide mixtures with different proportions of each peptide (1:0, 3:1, 1:1, 1:3, and 0:1) using TDA and atomic force microscopy (AFM). TDA allowed for monitoring the kinetics of the amyloid assembly and quantifying the transient intermediates. Complementarily, AFM allowed the formation of insoluble fibrils to be visualized. Together, the two techniques enabled us to study the influence of the peptide ratios on the kinetics and the formation of potentially toxic oligomeric species.

An increase in fatty acid indices in cerebrospinal fluid of mild cognitive impairment precedes a decrease in Alzheimer’s

AbstractBackgroundProcessing of membrane‐bound amyloid precursor protein (APP) may produce toxic amyloidogenic or less toxic non‐amyloidogenic amyloid (Aβ) peptides. We propose that brain membrane lipid composition and metabolism can dictate APP processing.MethodUsing neuropsychology measures, brain MRI, and consensus clinical conferencing, we classify three groups of elderly subjects: cognitively healthy (CH, n=70), mild cognitive impairment (MCI, n=40), and Alzheimer’s disease (AD, n=25). We fractionated CSF and determined the fatty acid composition of the unesterified fatty acid (UFA), the supernatant fluid (SF), and the nanoparticulate (NP) fraction using gas chromatography coupled with negative ion/chemical ionization mass spectrometry. We determined fatty acid indices for each fraction for chain length, unsaturation, peroxidation, and desaturase.ResultChain length, unsaturation, peroxidation, and desaturase indices were significantly different in the CSF fractions (p<0.0001). UFA carbon‐chain length, unsaturation, and peroxidation indices were higher in CH and MCI than in AD. In contrast, these indices did not significantly differ in the other CSF fractions. The UFA desaturase index was significantly higher in MCI (0.32±0.14) than in CH (0.26±0.2, adjusted p‐value (q) = 0.0220)) and AD (0.16±0.11, q <0.0001). In the SF and NP fractions, the desaturase index was lower in AD than MCI and CH. The changes in fatty acid indices were not associated with age, sex, BMI, and ApoE genotype.ConclusionOur studies show the compartmentalization of fatty acid metabolism in CSF fractions and changes in the AD spectrum. A higher carbon chain length, unsaturation, peroxidation, and desaturase index in MCI suggest higher lipid membrane turnover. A lower desaturase, peroxidase, and desaturase index in AD suggests enhanced lipolysis and oxidation of lipids. These data suggest that lipolysis and oxidation are features of AD pathophysiology, and monitoring fatty acid indices can help effectively monitor new therapies.