Search Results (111)

Previous studies have shown that plasma amyloid-beta oligomers (AβOs), the toxic form of amyloid-beta (Aβ), are a critical issue in the development or worsening of Alzheimer’s disease (AD) and can be regarded as a blood marker for screening in dementia. We examined plasma AβOs with their related biomarkers in a case–control study to clarify these issues. A total of 16 patients diagnosed with Alzheimer’s dementia (AD) and 16 cognitively normal controls (NCs) were recruited to compare their plasma biomarkers, AβO, Aβ_1-40, and Aβ_1-42, also referring to other parameters like APOE ε4 status, Clinical Dementia Rating^®-Sum of Boxes (CDR^®-SB), and Mini Mental Status Examination (MMSE) scores. In plasma concentrations of Aβ_1-40, Aβ_1-42, and AβO, the mean concentrations were significantly different between the two groups. There is a significant increase in the concentrations of Aβ_1-40 and AβO, while Aβ_1-42 is decreased in individuals with AD compared to NC. AβO was statistically associated with the Aβ_1-40 and Aβ_1-42/Aβ_1-40 ratio. Higher plasma concentrations of AβO were significantly associated with AD compared to non-dementia controls. This suggests that AβOs can be potential plasma biomarkers to screen in AD. However, a study recruiting more individuals is necessary to examine the association, if any. Full article

Alzheimer’s disease is characterized by the accumulation of neurotoxic forms of amyloid-beta (Aβ) in the brain, leading to synaptic dysfunction, neuroinflammation, and neuronal death. The tetrapeptide HAEE crosses the blood–brain barrier (BBB), inhibits the formation of toxic Aβ oligomers, and reduces amyloid burden in vivo. However, the mechanisms of HAEE’s anti-amyloidogenic effect remained incompletely understood. In this study, we investigated the mechanism of HAEE-dependent Aβ clearance both in vitro and in vivo. Using ELISA, we assessed the HAEE effect on the levels of Aβ, IL-6, and TNFα in mouse brain tissue following intracerebroventricular administration. The mechanism of the anti-Aβ effect of HAEE was studied using primary brain cell cultures and a BBB transwell model through ELISA, flow cytometry, and microscopy. We showed that HAEE reduced Aβ level by 35% and IL-6 level by 40% in mouse brain tissue. HAEE enhanced Aβ clearance via LRP1- and PgP-dependent Aβ transport through the BBB and doubled the rate of Aβ degradation by microglia. In addition to inhibition of Aβ aggregation, HAEE dissolved already formed Aβ oligomers. The HAEE-induced decrease in IL-6 levels in the mouse brain was associated with reduced pro-inflammatory activation of microglia. Thus, HAEE’s effect against Aβ-related neuropathologies is realized through a decrease in the level of toxic Aβ oligomer and inhibition of neuroinflammation. Full article

Abnormal accumulation of amyloid-beta (Aβ) peptides in the brain is a hallmark of Alzheimer’s disease (AD). Importantly, the peripheral blood cells are also exposed to the effects of pathological peptides that accumulate in AD. Herein, the interaction of Aβ42 oligomers (Aβ42) with human red blood cells (RBCs) and erythrocyte ghosts as in vitro models for AD is studied combining fluorescence spectroscopy, fluorescence microscopy, and electrokinetics. The binding of Aβ42 to RBCs was evidenced by the use of a fluorescent-labeled peptide. The membrane lipid order increased with the increase in both the Aβ42 concentration and the incubation time, creating a lipid–protein microenvironment characterized by higher molecular order and reduced heterogeneity in RBC membranes compared to control conditions. Notably, the increase in lipid order was less pronounced in erythrocyte ghosts than in intact RBCs. Furthermore, the ζ-potential measurements revealed Aβ42 induced alteration of the surface potential of RBCs in a concentration- and time-dependent manner, with freshly isolated RBCs exhibiting a highly negative potential that became increasingly negative at higher Aβ42 concentrations. These findings suggest that Aβ42 not only impacts neuronal function but also significantly alters the physical properties of RBCs that might compromise their function, potentially contributing to the systemic effects observed in AD. Full article

Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer’s disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21–23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity. Full article

Alzheimer’s disease (AD) instantly requires affordable diagnostic tools for targeting the responsible molecular biomarkers. In this review, we briefly discussed the overview of the AD population, performance of different analytical techniques and nanoparticles/composites, molecular biomarkers, and the interest of countries towards the detection of AD biomarkers during 2012–2025. The desired result was attained by lateral flow assay, surface-enhanced Raman scattering, and colorimetric sensor techniques with nanoparticles of magnetic, gold, and carbon-containing silver, and iridium oxide nanoparticles, upon biomarkers of dopamine, amyloid beta41, and Apolipoprotein E, individually. Additionally, the outstanding performance of nanoparticles including gold nanoparticles, carbon-containing nanoparticles, and manganese dioxide with their particle size of 5.7 nm, 35 nm, 37.3 nm, 120 nm, and 220 nm, respectively, has been discussed. Moreover, the percentages of AD-related biomarkers including amyloid beta42 having research articles of 21.2%, amyloid beta1-42 12.1%, amyloid beta oligomer 12.1%, phosphorylated Tau detection 12.1%, amyloid beta1-40 9.09%, Dopamine 9.09%, amyloid beta40 9.17%, apolipoprotein 6.06%, etc., have also been included. Additionally, LOD comparison with respect to applied analytical techniques, investigated through a timeline and electrochemical sensor, was found most suitable. Finally, a portable molecular diagnostic device to combine amyloid beta1-42, amyloid beta1-40, and phosphorylated Tau detection in non-invasive bodily fluid was proposed for the future and clinical diagnosis. Full article

The Sarco Endoplasmic Reticulum Ca²⁺-ATPase (SERCA) pumps cytosolic Ca²⁺ into the endoplasmic reticulum lumen (ER) to maintain cytosolic and ER Ca²⁺ levels under physiological conditions. Previous reports suggest that cellular Ca²⁺ homeostasis is compromised in Alzheimer’s Disease (AD) and that SERCA activity can modulate the phenotype of AD mouse models. Here, we used a C. elegans strain that overexpresses the most toxic human ß-amyloid peptide (Aß_(1-42)) in body-wall muscle cells to study the effects of SERCA (sca-1) silencing on Aß_(1-42)-induced body-wall muscle dysfunction. sca-1 knockdown reduced the percentage of paralyzed worms, improved locomotion in free-mobility assays, and restored pharynx pumping in Aß_(1-42)-overexpressing worms. At the cellular level, sca-1 silencing partially prevented Aß_(1-42)-induced exacerbated mitochondrial respiration and mitochondrial ROS production and restored mitochondrial organization around sarcomeres. sca-1 knockdown reduced the number and size of Aß_(1-42) aggregates in body–wall muscle cells and prevented the formation of Aß_(1-42) oligomers. Aß_(1-42) expression induced a slower kinetics of spontaneous cytosolic Ca²⁺ transients in muscle cells and sca-1 partially restored these changes. We propose that partial sca-1 loss of function prevents the toxicity associated with beta-amyloid accumulation by reducing the formation of Aß_(1-42) oligomers and improving mitochondrial function, in a mechanism that requires remodeling of cytosolic Ca²⁺ dynamics and partial ER Ca²⁺ depletion. Full article

The amyloid-beta 1-42 (Aβ1-42) oligomers are the most cytotoxic species of the amyloid family and play a key role in the pathology of Alzheimer’s Disease (AD). They have been shown to damage cellular membranes, but the exact mechanism is complex and not well understood. Multiple routes of membrane damage have been proposed, including the formation of pores and ion channels. In this work, we study the membrane damage induced by Aβ1-42 oligomers using black lipid membrane (BLM) electrophysiology and compare their action with gramicidin, known to form ion channels. Our data show that Aβ1-42 oligomers can induce a variety of damage in the lipid membranes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and cholesterol (CHOL), including small ion channels, similar to the gramicidin channels, with an average inner diameter smaller than 5 Å. These channels have a short retaining time in lipid membranes, suggesting that they are highly dynamic. Our studies provide new insights into the mechanism of membrane damage caused by Aβ1-42 oligomers and extend the current perception of the Aβ channelopathy hypothesis. It provides a more in-depth understanding of the molecular mechanism by which small Aβ oligomers induce cytotoxicity by interacting with lipid membranes in AD. Full article

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by the formation of neurotoxic beta-amyloid (Aβ) oligomers in the central nervous system. One of the earliest pathological effects of Aβ is the induction of oxidative stress in brain tissue, mediated by NADPH oxidase 2 (NOX2). This study aimed to determine whether short-term inhibition of NOX2 could disrupt the pathological cascade and prevent the development of Aβ-induced pathology. We demonstrated that suppressing NOX2 activity by GSK2795039 during the first three days after intracerebral Aβ administration prevented the development of the pathological process in mice. Two weeks after the induction of Aβ pathology, animals treated with GSK2795039 showed no neuropsychiatric-like behavioral changes, which correlated with the absence of chronic oxidative damage in brain tissue. Moreover, GSK2795039 prevented microglial activation and reduced microglia-associated neuroinflammation. These findings indicate that short-term NOX2 inhibition effectively suppresses the development of Aβ-induced pathology, suggesting that NOX2 is a potential target for treatment and prevention of AD pathology. Full article

Gelsemine, a naturally occurring indole alkaloid derived from plants of the Gelsemium species of the Gelsemiaceae family, has been extensively investigated for its neuroprotective and anti-inflammatory properties. Recent studies have demonstrated that gelsemine exerts neuroprotective effects against beta-amyloid (Aβ) oligomers, a key neurotoxic peptide implicated in the pathogenesis of Alzheimer’s disease (AD). However, despite these beneficial effects, the precise molecular targets underlying gelsemine’s neuroprotective actions in AD remain unidentified. Here, we employed a combination of bioinformatic, biochemical, and functional assays in neuronal models to investigate the mechanism of gelsemine’s action in AD cellular models. Our findings indicate that gelsemine inhibits the activity of transglutaminase 2 (TG2), an enzyme involved in protein cross-linking with emerging roles in Aβ aggregation and neurotoxicity. Molecular modeling and biochemical analyses reveal that gelsemine interacts with the TG2 catalytic site, leading to its inhibition. Furthermore, gelsemine modulates the TG2-mediated Aβ aggregation process, thereby attenuating Aβ-induced neurotoxicity and preserving neuronal function. These findings establish TG2 as a previously unrecognized molecular target of gelsemine and underscore the potential of Gelsemium-derived alkaloids as neuroprotective agents. The modulation of TG2 activity by natural alkaloids may provide a novel therapeutic approach for mitigating Aβ toxicity and preserving neuronal function in AD. Full article

Mitochondria possess a double-membrane envelope which is susceptible to insult by pathogenic intracellular aggregates of amyloid-forming peptides, such as the amyloid-beta (1-42) (Aβ42) peptide and the human islet amyloid polypeptide (hIAPP). The molecular composition of membranes plays a pivotal role in regulating peptide aggregation and cytotoxicity. Therefore, we hypothesized that modifying the physicochemical properties of mitochondrial model membranes with a small molecule might act as a countermeasure against the formation of, and damage by, membrane-active amyloid peptides. To investigate this, we inserted the natural ubiquinone Coenzyme Q10 (CoQ10) in model mito-mimetic lipid vesicles, and studied how they interacted with Aβ42 and hIAPP peptide monomers and oligomers. Our results demonstrate that the membrane incorporation of CoQ10 significantly attenuated fibrillization of the peptides, whilst also making the membranes more resilient against peptide-induced permeabilization. Furthermore, these protective effects were linked with the ability of CoQ10 to enhance membrane packing in the inner acyl chain region, which increased the mechanical stability of the vesicle membranes. Based on our collective observations, we propose that mitochondrial resilience against toxic biomolecules implicit in protein misfolding disorders such as Alzheimer’s disease and type-2 diabetes, could potentially be enhanced by increasing CoQ10 levels within mitochondria. Full article

Intrinsically disordered proteins (IDPs), such as tau, beta-amyloid (Aβ), and alpha-synuclein (αSyn), are prone to misfolding, resulting in pathological aggregation and propagation that drive neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). Misfolded IDPs are prone to aggregate into oligomers and fibrils, exacerbating disease progression by disrupting cellular functions in the central nervous system, triggering neuroinflammation and neurodegeneration. Furthermore, aggregated IDPs exhibit prion-like behavior, acting as seeds that are released into the extracellular space, taken up by neighboring cells, and have a propagating pathology across different regions of the brain. Conventional inhibitors, such as small molecules, peptides, and antibodies, face challenges in stability and blood–brain barrier penetration, limiting their efficacy. In recent years, nanotechnology-based strategies, such as multifunctional nanoplatforms or nanoparticles, have emerged as promising tools to address these challenges. These nanoplatforms leverage tailored designs to prevent or remodel the aggregation of IDPs and reduce associated neurotoxicity. This review discusses recent advances in nanoplatforms designed to target tau, Aβ, and αSyn aggregation, with a focus on their roles in reducing neuroinflammation and neurodegeneration. We examine critical aspects of nanoplatform design, including the choice of material backbone and targeting moieties, which influence interactions with IDPs. We also highlight key mechanisms including the interaction between nanoplatforms and IDPs to inhibit their aggregation, redirect aggregation cascade towards nontoxic, off-pathway species, and disrupt fibrillar structures into soluble forms. We further outline future directions for enhancing IDP clearance, achieving spatiotemporal control, and improving cell-specific targeting. These nanomedicine strategies offer compelling paths forward for developing more effective and targeted therapies for neurodegenerative diseases. Full article

Alzheimer’s disease (AD) is a neurodegenerative disease marked by the accumulation of toxic amyloid-beta (Aβ) oligomers. These oligomers are thought to cause synaptic dysfunction and contribute to neurodegeneration. CT1812 is a small-molecule sigma-2 receptor antagonist that is currently being investigated and tested as a potential disease-modifying treatment for AD. CT1812 acts by displacing Aβ oligomers into the cerebrospinal fluid and preventing their interaction with receptors on neurons. Preclinical studies and early clinical trials of CT1812 show promising results and provide evidence for its potential to slow AD progression. This review outlines the role of Aβ oligomers in AD, CT1812’s mechanism of action, and the effectiveness and limitations of CT1812 based on preclinical and clinical studies. Full article

Background: Choroid plexus is a complex structure in the human brain that is responsible for the secretion of extracellular vesicles (EVs) in cerebrospinal fluid. Few studies to date have generated choroid plexus (ChP) organoids differentiated from human induced pluripotent stem cells (hiPSCs) and analyzed their secreted EVs. The scalable Vertical-Wheel bioreactors (VWBRs) provide low shear stress and a controlled environment. Methods: This study utilized VWBRs for the differentiation of hiPSCs into ChP organoids and generation of the secreted EVs compared to a static culture. Additionally, this study loaded curcumin into ChP organoid-derived EVs, performed EV lyophilization, and determined the ability of the re-hydrated EVs to alleviate neuro-inflammation. Results: The results demonstrated that the VWBR culture exhibited more aerobic metabolism and active glucose and glutamine consumption than the static control. Consequently, the ChP markers and Endosomal Sorting Complexes Required for Transport-dependent and -independent EV biogenesis genes were significantly upregulated (2–3-fold) in the VWBR, producing four-fold-higher EVs per mL media than the static control. The EVs retained similar size and zeta potential after lyophilization and re-hydration. The cells exposed to amyloid beta 42 oligomers and treated with the curcumin-loaded re-hydrated EVs showed high viability and the reduced inflammatory response determined by TNF-α and IL-6 expression. Conclusions: This study demonstrates a scalable bioreactor system to promote ChP organoid differentiation and generation of EV-based cell-free therapeutics to treat neural inflammation in various neurological disorders. Full article

The amyloid hypothesis is the predominant model of Alzheimer’s disease (AD) pathogenesis, suggesting that amyloid beta (Aβ) peptide is the primary driver of neurotoxicity and a cascade of pathological events in the central nervous system. Aβ aggregation into oligomers and deposits triggers various processes, such as vascular damage, inflammation-induced astrocyte and microglia activation, disrupted neuronal ionic homeostasis, oxidative stress, abnormal kinase and phosphatase activity, tau phosphorylation, neurofibrillary tangle formation, cognitive dysfunction, synaptic loss, cell death, and, ultimately, dementia. Molecular dynamics (MD) is a powerful structure-based drug design (SBDD) approach that aids in understanding the properties, functions, and mechanisms of action or inhibition of biomolecules. As the only method capable of simulating atomic-level internal motions, MD provides unique insights that cannot be obtained through other techniques. Integrating experimental data with MD simulations allows for a more comprehensive understanding of biological processes and molecular interactions. This review summarizes and evaluates MD studies from the past decade on small molecules, including endogenous compounds and repurposed drugs, that inhibit amyloid beta. Furthermore, it outlines key considerations for future MD simulations of amyloid inhibitors, offering a potential framework for studies aimed at elucidating the mechanisms of amyloid beta inhibition by small molecules. Full article

Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer’s disease (AD); α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington’s disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics. Full article