Search Results (1,148)

Investigating amyloid–β (Aβ) peptides in solution is essential during the initial stages of developing lead compounds that can influence Aβ fibrillation while the peptide is still in a soluble state. The tendency of the Aβ(1–42) peptide to misfold in solution, correlated to the aetiology of Alzheimer’s disease (AD), is one of the main hindrances to characterising its aggregation kinetics in a cell-mimetic environment. Moreover, the Aβ(1–42) aggregation triggers the unfolded protein response (UPR) in the endoplasmic reticulum (ER), leading to cellular dysfunction and multiple cell death modalities, exacerbated by reactive oxygen species (ROS), which damage cellular components and trigger inflammation. Antioxidants like curcumin, a derivative of Curcuma longa, help mitigate ER stress by scavenging ROS and enhancing antioxidant enzymes. Furthermore, evidence in the literature highlights the effect of curcumin on the secondary structure of Aβ(1–42). This explorative study investigates the Aβ(1–42) peptide conformational behaviour in the presence of curcumin and six derivatives using circular dichroism (CD) to explore their interactions with lipid bilayers, potentially preventing aggregate formation. The results suggest that the synthetic tetrahydrocurcumin (THC) derivative interacts with the amyloid peptide in all the systems presented, while cyclocurcumin (CYC) and bisdemethoxycurcumin (BMDC) only interact when the peptide is in a less stable conformation. Molecular dynamics simulations helped visualise the curcuminoids’ effect in an aqueous system and hypothesise the importance of the peptide surface exposition to the solvent, differently modulated by the curcumin derivatives. Full article

A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer’s disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer’s research field. The present Perspective challenges this assumption. It analyses the relevant empirical data and reaches an unexpected conclusion, namely that in AD-afflicted neurons, the production of AβPP-derived Aβ is either discontinued or severely suppressed, a concept that, if proven, would fundamentally change our understanding of the disease. This suppression, effectively self-suppression, occurs in the context of the global inhibition of the cellular cap-dependent protein synthesis as a consequence of the neuronal integrated stress response (ISR) elicited by AβPP-derived intraneuronal Aβ (iAβ; hence self-suppression) upon reaching certain levels. Concurrently with the suppression of the AβPP proteolytic pathway, the neuronal ISR activates in human neurons, but not in mouse neurons, the powerful AD-driving pathway generating the C99 fragment of AβPP independently of AβPP. The present study describes molecular mechanisms potentially involved in these phenomena, propounds novel approaches to generate transgenic animal models of AD, advocates for the utilization of human neuronal cells-based models of the disease, makes verifiable predictions, suggests experiments designed to validate the proposed concept, and considers its potential research and therapeutic implications. Remarkably, it opens up the possibility that the conventional production of AβPP, BACE enzymes, and γ-secretase components is also suppressed under the neuronal ISR conditions in AD-affected neurons, resulting in the dyshomeostasis of AβPP. It follows that whereas conventional AD is triggered by AβPP-derived iAβ accumulated to the ISR-eliciting levels, the disease, in its both conventional and unconventional (triggered by the neuronal ISR-eliciting stressors distinct from iAβ) forms, is driven not (or not only) by iAβ produced in the AβPP-independent pathway, as we proposed previously, but mainly, possibly exclusively, by the C99 fragment generated independently of AβPP and not cleaved at the γ-site due to the neuronal ISR-caused deficiency of γ-secretase (apparently, the AD-driving “substance X” predicted in our previous study), a paradigm consistent with a dictum by George Perry that Aβ is “central but not causative” in AD. The proposed therapeutic strategies would not only deplete the driver of the disease and abrogate the AβPP-independent production of C99 but also reverse the neuronal ISR and ameliorate the AβPP dyshomeostasis, a potentially significant contributor to AD pathology. Full article

Lipopolysaccharides (LPS) are bacterial mediators of neuroinflammation that have been detected in close association with pathological protein aggregations of Alzheimer’s disease. LPS induce the release of cytokines by microglia and mediate the upregulation of inducible nitric oxide synthase (iNOS)—a mechanism also associated with amyloidosis. Curcumin is a recognized natural medicine but has extremely low bioavailability. V-Cur, a novel hemocompatible Vanadium(IV)-curcumin complex with higher solubility and bioactivity than curcumin, is studied here. Co-cultures consisting of rat primary neurons and microglia were treated with LPS and/or curcumin or V-Cur. V-Cur disrupted LPS-induced overexpression of amyloid precursor protein (APP) and the in vitro aggregation of human insulin (HI), more effectively than curcumin. Cell stimulation with LPS also increased full-length, inactive, and total iNOS levels, and the inflammation markers IL-1β and TNF-α. Both curcumin and V-Cur alleviated these effects, with V-Cur reducing iNOS levels more than curcumin. Complementary insights into possible bioactivity mechanisms of both curcumin and V-Cur were provided by In silico molecular docking calculations on Aβ_1-42, APP, Aβ fibrils, HI, and iNOS. This study renders curcumin-based compounds a promising anti-inflammatory intervention that may be proven a strong tool in the effort to mitigate neurodegenerative disease pathology and neuroinflammatory conditions. Full article

Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by extracellular amyloid plaques, predominantly consisting of amyloid-β (Aβ) peptides. The oligomeric form of Aβ is acknowledged as the most neurotoxic, propelling the pathological progression of AD. Interestingly, besides Aβ, other proteins are co-localized within amyloid plaques. Peptide analogs corresponding to the “aggregation-prone” regions (APRs) of these proteins could exhibit high-affinity binding to Aβ and significant inhibitory potential against the Aβ oligomerization process. The peptide analogs of co-localized protease, Cathepsin B, may act as such potent inhibitors. In silico studies on the complexes of the oligomeric state of Aβ and Cathepsin B peptide analogs were performed utilizing molecular docking and molecular dynamics simulations, revealing that these analogs disrupt the β-sheet-rich core of Aβ oligomers, a critical structural feature of their stability. Of the four peptide analogs evaluated, two demonstrated considerable potential by effectively destabilizing oligomers while maintaining low self-aggregation propensity, i.e., a crucial consideration for therapeutic safety. These findings point out the potential of APR-derived peptide analogs from co-localized proteins as innovative agents against AD, paving the way for further exploration in peptide-based therapeutic development. Full article

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer’s disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder marked by the progressive accumulation of amyloid-β (Aβ) plaques and tau protein tangles in the brain. These pathological aggregates interfere with neuronal function, leading to the disruption of cognitive processes, particularly memory. The deposition of Aβ forms senile plaques, while tau protein, in its hyperphosphorylated state, forms neurofibrillary tangles, both of which contribute to the underlying neurodegeneration observed in AD. Rosmarinic acid (RosA), a natural compound found in plants such as Rosmarinus officinalis, is known for its antioxidant, anti-inflammatory, and antimicrobial properties. Due to its ability to cross the blood–brain barrier, RosA holds promise as a nutritional supplement that may support brain health. In this study, molecular dynamics (MD) simulations were used to investigate the impact of RosA on the structural stability of Aβ peptides. The results indicated that the addition of RosA increased the instability of Aβ, as evidenced by an increase in the Root Mean Square Deviation (RMSD), a decrease in the Radius of Gyration (Rg), and an expansion of the Solvent Accessible Surface Area (SASA). This destabilization is primarily attributed to the disruption of native hydrogen bonds and hydrophobic interactions in the presence of two RosA molecules. The free energy landscape (FEL) analysis and MM-PBSA (Poisson-Boltzmann Surface Area Mechanics) results further support the notion that RosA can effectively bind to the hydrophobic pocket of the protein, highlighting its potential as a nutritional component that may contribute to maintaining brain health and function. Full article

Background: A limited number of studies have investigated the role of environmental chemicals in the etiology of mild cognitive impairment (MCI). We performed a cross-sectional study of the association between exposure to selected trace elements and the biomarkers of cognitive decline. Methods: During 2019–2021, we recruited 128 newly diagnosed patients with MCI from two Neurology Clinics in Northern Italy, i.e., Modena and Reggio Emilia. At baseline, we measured serum and cerebrospinal fluid (CSF) concentrations of cadmium, copper, iron, manganese, and zinc using inductively coupled plasma mass spectrometry. With immuno-enzymatic assays, we estimated concentrations of β-amyloid 1-40, β-amyloid 1-42, Total Tau and phosphorylated Tau181 proteins, neurofilament light chain (NfL), and the mini-mental state examination (MMSE) to assess cognitive status. We used spline regression to explore the shape of the association between exposure and each endpoint, adjusted for age at diagnosis, educational attainment, MMSE, and sex. Results: In analyses between the serum and CSF concentrations of trace metals, we found monotonic positive correlations between copper and zinc, while an inverse association was observed for cadmium. Serum cadmium concentrations were inversely associated with amyloid ratio and positively associated with Tau proteins. Serum iron concentrations showed the opposite trend, while copper, manganese, and zinc displayed heterogeneous non-linear associations with amyloid ratio and Tau biomarkers. Regarding CSF exposure biomarkers, only cadmium consistently showed an inverse association with amyloid ratio, while iron was positively associated with Tau. Cadmium concentrations in CSF were not appreciably associated with serum NfL levels, while we observed an inverted U-shaped association with CSF NfL, similar to that observed for copper. In CSF, zinc was the only trace element positively associated with NfL at high concentrations. Conclusions: In this cross-sectional study, high serum cadmium concentrations were associated with selected biomarkers of cognitive impairment. Findings for the other trace elements were difficult to interpret, showing complex and inconsistent associations with the neurodegenerative endpoints examined. Full article

Bgl2p is a major, conservative, constitutive glucanosyltransglycosylase of the yeast cell wall (CW) with amyloid amino acid sequences, strongly non-covalently anchored in CW, but is able to leave it. In the environment, Bgl2p can form fibrils and/or participate in biofilm formation. Despite a long study, the question of how Bgl2p is anchored in CW remains unclear. Earlier, it was demonstrated that Bgl2p lost the ability to attach in CW and to fibrillate after the deletion of nine amino acids in its C-terminal region (CTR). Here, we demonstrated that a Bgl2p anchoring is weakened by substitution Glu-233/Ala in the active center. Using AlphaFold and molecular modeling approach, we demonstrated the role of CTR on Bgl2p attachment and supposed the conformational possibilities determined by the presence or absence of an intramolecular disulfide bond, forming by Cys-310, leading to accessibility of amyloid sequence and β-turns localized in CTR of Bgl2p for protein interactions. We hypothesized the mode of Bgl2p attachment in CW. Using atomic force microscopy, we investigated fibrillar structures formed by peptide V187MANAFSYWQ196 and suggested that it can serve as a factor leading to the induction of amyloid formation during interaction of Bgl2p with other proteins and is of medical interest being located close to the surface of the molecule. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management. Full article

Nanopipettes, as a class of solid-state nanopores, have evolved into universal tools in biomedicine for the detection of biomarkers and different biological analytes. Nanopipette-based methods combine high sensitivity, selectivity, single-molecule resolution, and multifunctionality. The features have significantly expanded interest in their applications for the biomolecular detection, imaging, and molecular diagnostics of real samples. Moreover, the ease of manufacturing nanopipettes, coupled with their compatibility with fluorescence and electrochemical methods, makes them ideal for portable point-of-care diagnostic devices. This review summarized the latest progress in nanopipette-based nanopore technology for the detection of biomarkers, DNA, RNA, proteins, and peptides, in particular β-amyloid or α-synuclein, emphasizing the impact of technology on molecular diagnostics. By addressing key challenges in single-molecule detection and expanding applications in diverse biological areas, nanopipettes are poised to play a transformative role in the future of personalized medicine. Full article

Alzheimer’s disease is one of the most common neurodegenerative diseases, characterized by a wide range of neurological symptoms that begin with personality changes and psychiatric symptoms, progress to mild cognitive impairment, and eventually lead to dementia. Physical exercise is part of the non-pharmacological treatments used in Alzheimer’s disease, as it has been shown to delay the neurodegenerative process by improving the redox state in brain tissue, providing anti-inflammatory effects or stimulating the release of the brain-derived neurotrophic factor that enhances the brain structure and cognitive performance. Here, we reviewed the results obtained from studies conducted in both animal models and human subjects to comprehend how physical exercise interventions can exert changes in the molecular mechanisms underlying the pathophysiological processes in Alzheimer’s disease: amyloid β-peptide pathology, tau pathology, neuroglial changes, mitochondrial dysfunction, and oxidative stress. Physical exercise seems to have a protective effect against Alzheimer’s disease, since it has been shown to induce positive changes in some of the biomarkers related to the pathophysiological processes of the disease. However, additional studies in humans are necessary to address the current lack of conclusive evidence. Full article

The fibronectin domain-containing protein 5 (FNDC5), or irisin, is an adipo-myokine hormone produced during exercise, which shows therapeutic potential for conditions like metabolic disorders, osteoporosis, sarcopenia, obesity, type 2 diabetes, and neurodegenerative diseases, including Alzheimer’s disease (AD). This review explores its potential across various pathophysiological processes that are often considered independent. Elevated in healthy states but reduced in diseases, irisin improves muscle–adipose communication, insulin sensitivity, and metabolic balance by enhancing mitochondrial function and reducing oxidative stress. It promotes osteogenesis and mitigates bone loss in osteoporosis and sarcopenia. Irisin exhibits anti-inflammatory effects by inhibiting NF-κB signaling and countering insulin resistance. In the brain, it reduces amyloid-β toxicity, inflammation, and oxidative stress, enhancing brain-derived neurotrophic factor (BDNF) signaling, which improves cognition and synaptic health in AD models. It also regulates dopamine pathways, potentially alleviating neuropsychiatric symptoms like depression and apathy. By linking physical activity to systemic health, irisin emphasizes its role in the muscle–bone–brain axis. Its multifaceted benefits highlight its potential as a therapeutic target for AD and related disorders, with applications in prevention, in treatment, and as a complement to exercise strategies. Full article

The hallmark of Alzheimer’s disease (AD) is the buildup of amyloid-β (Aβ), which is produced when the amyloid precursor protein (APP) misfolds and deposits as neurotoxic plaques in the brain. A functional iron responsive element (IRE) RNA stem loop is encoded by the APP 5′-UTR and may be a target for regulating the production of Alzheimer’s amyloid precursor protein. Since modifying Aβ protein expression can give anti-amyloid efficacy and protective brain iron balance, targeted regulation of amyloid protein synthesis through modulation of 5′-UTR sequence function is a novel method for the prospective therapy of Alzheimer’s disease. Numerous mRNA interference strategies target the 2D RNA structure, even though messenger RNAs like tRNAs and rRNAs can fold into complex, three-dimensional structures, adding even another level of complexity. The IRE family is among the few known 3D mRNA regulatory elements. This review seeks to describe the structural and functional aspects of IREs in transcripts, including that of the amyloid precursor protein, that are relevant to neurodegenerative diseases, including AD. The mRNAs encoding the proteins involved in iron metabolism are controlled by this family of similar base sequences. Like ferritin IRE RNA in their 5′-UTR, iron controls the production of APP in their 5′-UTR. Iron misregulation by iron regulatory proteins (IRPs) can also be investigated and contrasted using measurements of the expression levels of tau production, Aβ, and APP. The development of AD is aided by iron binding to Aβ, which promotes Aβ aggregation. The development of small chemical therapeutics to control IRE-modulated expression of APP is increasingly thought to target messenger RNAs. Thus, IRE-modulated APP expression in AD has important therapeutic implications by targeting mRNA structures. Full article

Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive impairment and Alzheimer’s dementia) neurodegenerative diseases. Limited efficacy of current pharmacological treatments warrants further search for new targets for nootropic interventions. The breakdown of myelin, a phospholipids axonal sheath that protects the conduction of nerve impulse between neurons, was proposed as a neuropathological abnormality that precedes and promotes the deposition of amyloid-β in neuritic plaques. The present review of the recent literature and our own pre- and clinical data suggest (for the first time) that the anthranilic acid (AA)-induced activation of microglial-expressed G-protein coupled receptor (GPR109A) inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that triggers the degradation of myelin and consequently attenuates cognitive impairment. The present review suggests that the up-regulation of AA formation is a sex-specific compensatory (adaptive) reaction aimed to prevent/treat cognitive impairment. The AA–GPR109A–cPLA2–myelin–cognition cascade suggests new nootropic interventions, e.g., the administration of pegylated kynureninase, an enzyme that catalyzes AA formation from Kynurenine (Kyn), a tryptophane catabolite; pegylated interferon-alpha; central and peripheral Kyn aminotransferase inhibitors that increase availability of Kyn as a substrate for AA formation; and vagus nerve stimulation. The cascade predicts nootropic activity of exogenous GPR109A agonists that were designed and underwent clinical trials (unsuccessful) as anti-dyslipidemia agents. The proposed cascade might contribute to the pathogenesis of cognitive impairment. Data on AA in neurodegenerative disorders are scarce, and the proposed cascade needs further exploration in pre- and clinical studies Full article