Search Results (890)

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) plaque accumulation and neurodegeneration. This study identified gyrophoric acid, a lichen-derived phenolic metabolite, as a dual-action Aβ42 inhibitor preventing aggregation and disassembling of mature Aβ42 fibrils. Integrated in silico studies revealed that gyrophoric acid was a strong thermodynamic stabilizer of Aβ42 (MM–GBSA: −27.3 kcal/mol) via entropically driven hydrophobic interactions and disruption of aggregation-prone conformations (100 ns MD simulations). Through biochemical analysis of the fluorescent dye thioflavin T (ThT), gyrophoric acid induced rapid Aβ42 fibril disassembly within 5 h, with time-lapse confocal microscopy quantitatively confirming the near-complete dissolution of large aggregates by 24 h. ADMET profiling revealed favorable pharmacokinetics (moderate oral absorption: 48.5–57.3%; low toxicity) and Lipinski’s rule compliance. These results establish gyrophoric acid as a promising natural bioactive compound for anti-AD therapeutics with a unique hydrophobic-stabilization mechanism. Full article

Background: Although Presenilin-1 (PSEN1) mutations are classically associated with early-onset Alzheimer’s disease (AD), spastic paraparesis (SP) may occasionally represent as an initial or even isolated clinical manifestation. Methods: We report the novel association of a PSEN1 mutation (Leu282Arg) with isolated SP at onset in a patient with a family history of early-onset AD. Additionally, we reviewed previously published cases describing similar presentations related to PSEN1 mutations. Results: The age of reported patients ranged from 24 to 60 years. The most common clinical course included the presence of cotton wool plaques and a progressive development of cognitive decline following the onset of SP. A positive family history of either motor or cognitive symptoms was consistently observed. Conclusions: Our findings emphasize the clinical importance of considering PSEN1 mutations in the differential diagnosis of patients presenting with spastic paraparesis, particularly in the presence of cognitive symptoms, cerebral amyloid angiopathy, or a family history of AD. Full article

Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuronal loss. Although amyloid-β plaques and neurofibrillary tangles have been the historical hallmarks of AD pathology, growing evidence highlights microglial-mediated neuroinflammation as a central driver of disease onset and progression. This review aims to provide an updated overview of the dual roles of microglia in AD, from their protective functions to their contribution to chronic inflammation and neurodegeneration. Methods: This review synthesizes findings from recent experimental and clinical studies to examine the molecular mechanisms underlying microglial activation and dysfunction in AD. Key areas of focus include microglial signaling pathways, gut–brain axis interactions, and immunometabolic regulation. The review also evaluates emerging immunomodulatory therapeutic strategies designed to restore microglial homeostasis. Results: Recent studies reveal that microglia undergo a dynamic transition from a homeostatic to a reactive state in AD, contributing to sustained neuroinflammation and impaired clearance of pathological aggregates. Molecular mechanisms such as TREM2 signaling, NLRP3 inflammasome activation, and metabolic reprogramming play critical roles in this process. Additionally, gut microbiota alterations and systemic inflammation have been shown to influence microglial function, further exacerbating disease pathology. Conclusions: Targeting microglial dysfunction through immunomodulatory strategies holds promise as a disease-modifying approach in AD. Therapeutic avenues under investigation include natural compounds, synthetic modulators, immunotherapies, and microbiota-based interventions. A deeper mechanistic understanding of microglial regulation may open new translational pathways for the development of effective treatments for AD. Full article

Alzheimer’s disease is the most common form of dementia, yet current treatments only offer symptomatic relief, with little preventative, therapeutic, or disease-modifying properties. As a result, there has been growing interest in targeting various disease mechanisms. One promising target is soluble epoxide hydrolase (sEH), an enzyme found in many organs, playing an important role in metabolism and detoxification. In the brain, sEH is mainly present in astrocytes, oligodendrocytes, and neuronal cell bodies, with higher concentrations in the cerebral cortex and striatum. The main function of sEH is the hydrolysis of epoxyeicosatrienoic acids (EETs), which are important anti-inflammatory molecules derived from arachidonic acid. Deletion of EPHX2, the encoding gene of sEH, maintains EET levels in the brain and helps mitigate inflammation. Multiple studies have found links between sEH function, inflammation, and neurodegeneration in Alzheimer’s disease. Several compounds, including TPPU, benzohomoadamantane derivatives, and natural products, have shown significant beneficial effects, including reduction of amyloid-beta plaques, tau fibrils, and inflammation, while improving cognition and neuronal structure and function. sEH inhibitors have also been explored for their potential in the management of Parkinson’s disease, vascular dementia, stroke, and other neurodegenerative conditions. Although these preclinical findings are promising, efficacy and safety concerns still need to be addressed, and further clinical trials are needed to translate these therapeutic agents into clinical practice. Full article

One hundred and eighteen years have passed since Alzheimer’s disease (AD) was first diagnosed by Alois Alzheimer as a multifactorial and complex neurodegenerative disorder with psychiatric components. It is inaugurated by a cascade of events initiating from amnesic-type memory impairment leading to the gradual loss of cognitive and executive capacities. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated tau protein aggregate in the brain. These pathological processes lead to neuronal loss, brain atrophy, and gliosis culminating in neurodegeneration and fueling AD. Thus, at a basic level, abnormality in the brain’s protein function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is an aging disorder caused by a combination of age-related changes and genetic and environmental factors that affect the brain over time. Its mysterious pathology seems not to be limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but to a plethora of substantial and biological processes, which have also emerged in its pathogenesis, such as a breakdown of the blood–brain barrier (BBB), patients carrying the gene variant APOE4, and the immuno-senescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) have also been observed to be early markers that may provoke pathogenic pathways that lead to or aggravate AD progression and pathology. There are numerous substantial AD features that require more understanding, such as chronic neuroinflammation, decreased glucose utilization and energy metabolism, as well as brain insulin resistance (IR). Herein, we aim to broaden our understanding and to connect the dots of the multiple comorbidities and their cumulative synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid-beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement, and the role of APOE4 allele and AD–IR pathogenic link—the shared genetics and metabolomic biomarkers between AD and IR disorders. Investment in future research brings us closer to knowing the pathogenesis of AD and paves the way to building prevention and treatment strategies. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory loss and cognitive decline, which significantly impacts patients’ quality of life and imposes substantial emotional, practical, and economic burdens on their families. As the most common cause of senile dementia, AD currently affects approximately 50 million people worldwide, with projections indicating a threefold increase by 2050 due to rising life expectancy and an aging global population. Diagnosis of AD remains challenging. Neuroimaging techniques reveal atrophy in critical brain regions, particularly in the cortex, hippocampus, and limbic system, which are essential substrates for memory, personality changes, and other cognitive functions. The hallmark molecular changes associated with AD include the accumulation of β-amyloid plaques and the formation of tau protein tangles. Several underlying mechanisms contribute to neuron loss, such as oxidative stress, neuroinflammation, microbial dysbiosis, and insulin resistance. In this context, exosomes—small extracellular vesicles that facilitate cell communication—transport proteins, DNA, mRNA, and non-coding RNA (ncRNA), all of which play a significant role in the neurobiology of AD. Furthermore, emerging research indicates that exosomal ncRNAs may serve as promising biomarkers for AD, offering the possibility of improved diagnostic precision. This review explores the potential of exosomal ncRNAs—specifically circular RNAs and microRNAS—as non-invasive biomarkers for AD, highlighting recent advances and future directions in translational studies. Full article

Chronic inflammation underpins the pathogenesis of both rheumatoid arthritis (RA) and neurodegenerative conditions such as Alzheimer’s disease (AD). This narrative review explores the role of C-reactive protein (CRP), particularly its monomeric form (mCRP), as a central molecular link connecting systemic autoimmune inflammation with neuroinflammatory and vascular pathology. In RA, fibroblast-like synoviocytes (FLSs) are activated by CRP through CD32/CD64-mediated signaling, triggering proinflammatory cascades involving NF-κB and p38 MAPK. Recent studies have highlighted that locally synthesized CRP within the synovium may convert to mCRP, amplifying inflammation and tissue damage. Beyond RA, mCRP has been identified within amyloid-beta (Aβ) plaques in AD brains, suggesting a direct role in neurodegenerative pathology. Experimental models also demonstrate that mCRP is upregulated in stroke-affected brain regions and associated with complement activation and blood–brain barrier (BBB) disruption, which is central to AD progression. The convergence of pathways involving IL-6, RAGE (receptor for advanced glycation end-products), and mCRP-mediated complement activation reveals a shared axis of inflammation between RA and AD. This highlights the potential of mCRP not only as a biomarker of chronic inflammation but also as a therapeutic target. Furthermore, evidence from periodontal disease and cardiovascular comorbidities highlights the systemic nature of mCRP-driven inflammation, offering insights into the mechanisms of disease overlap. This review advocates for further mechanistic studies into mCRP signaling, particularly its role at the interface of systemic and neuroinflammation, with the goal of identifying new interventional strategies for patients with RA at elevated risk of neurodegenerative and vascular complications. Full article

Alzheimer’s disease (AD), a prevalent neurodegenerative disorder in the aging population, remains without definitive therapeutic solutions. Emerging insights into the gut microbiota (GM) and its bidirectional communication with the central nervous system(CNS) through the microbiota–gut–brain axis (MGBA) have unveiled potential correlative mechanisms that may contribute to AD pathogenesis, though causal evidence remains limited. Dysregulation of GM composition (dysbiosis) exacerbates AD progression via neuroinflammation, amyloid-β (Aβ) deposition, and tau hyperphosphorylation (p-tau), while restoring microbial homeostasis presents a promising therapeutic strategy. Fecal microbiota transplantation (FMT), a technique to reconstitute gut ecology by transferring processed fecal matter from healthy donors, has demonstrated efficacy in ameliorating cognitive deficits and neuropathology in AD animal models. Preclinical studies reveal that FMT reduces Aβ plaques, normalizes tau phosphorylation, suppresses inflammasome activation, and restores microglial homeostasis through modulation of microbial metabolites and immune pathways. Although clinical evidence remains limited to case reports and small-scale trials showing potential therapeutic effect, safety concerns regarding long-term effects and protocol standardization necessitate further investigation. This review synthesizes current knowledge on GM–AD interactions, evaluates FMT’s mechanistic potential, and discusses challenges in translating this ancient practice into a cutting-edge AD therapy. Rigorous randomized controlled trials and personalized microbiota-based interventions are imperative to advance FMT from bench to bedside. Full article

Background: Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative disorders and the most common form of dementia. Although current treatments examine disease progression, many have side effects and primarily target symptomatic relief as opposed to halting further neurodegeneration. Objective: The current study aims to determine the neuroprotective effects of water-soluble coenzyme Q10 (Ubisol-Q10) and an ethanolic Ashwagandha extract (E-ASH) on a transgenic mouse model of AD. Methods: A variety of immunofluorescence staining of biomarkers was conducted to assess mechanisms commonly implicated in the disease. Additionally, spatial and non-spatial memory tests evaluated cognitive functions at two timepoints throughout the progression of the disease. Results: A substantial reduction in microglial activation and amyloid-β (Aβ) plaques when treated with a combination of natural health products (NHPs), Ubisol-Q10 and E-ASH. Moreover, activation of autophagy was upregulated in both the Ubisol-Q10 and combination (Ubisol-Q10+E-ASH given as a combined “Tonic” solution) groups. Oxidative stress was decreased across treated groups, while astrocyte activation was elevated in both the E-ASH and Tonic group. The Tonic group expressed an elevation in the fluorescent intensity of neuronal nuclei (NeuN) and brain-derived neurotrophic factor (BDNF) levels. Interestingly, treatment with E-ASH and Ubisol-Q10 enhanced synaptic vesicle formation compared to controls. Pre-mortem memory tests revealed the treatments to be effective at preserving cognitive abilities. Conclusions: Based on these findings, the combination of E-ASH and Ubisol-Q10 may effectively mitigate the various mechanisms implicated in AD and ultimately prevent further disease progression. Full article

Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34⁺ HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer’s disease (AD), the APPswe/PS1dE9 mouse. At 12 months of age, mice received intracisternal injections of NC (1.39 × 10⁶ MSCs + 5 × 10⁵ HSCs) or vehicle. After 45 days, behavioural testing, immunohistochemical analyses of amyloid plaque density (APD), and cortical gene expression profiling were conducted. NC-treated APP/PS1 mice exhibited preserved object recognition memory and reduced anxiety-like behaviours, contrasting with deficits observed in untreated transgenic controls. Histologically, NC treatment significantly reduced the density of small amyloid plaques (<50 μm²) in the hippocampus and thalamus, and total plaque burden in the thalamus. Gene expression analysis revealed that NC treatment normalised or reversed disease-associated changes in insulin receptor (IR) signalling and neurotrophic pathways. Specifically, NC increased expression of Bdnf, Irs2, and Pgc-1α, while attenuating aberrant upregulation of Insr, Igf1r, and markers of ageing and AD-related pathology (Sirt1, Gdf15, Arc, Egr1, Cldn5). These findings indicate that NC therapy mitigates behavioural and molecular hallmarks of AD, potentially via restoration of BDNF and insulin receptor-mediated signalling. Full article

Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, pathologically defined by the accumulation of amyloid-β plaques and tau-related neurofibrillary tangles in the brain. It represents a principal driver of cognitive deterioration in middle-aged and elderly populations. Early diagnosis and pharmacological management of the disease markedly improve both the quality and duration of life. Methods: Electroencephalography (EEG) is critical in detecting and analyzing Alzheimer’s disease. The widespread use of mobile EEG devices in recent years has necessitated real-time and effective data processing. However, extracting disease-specific features from EEG data still poses a significant challenge, especially in cases that must be completed quickly. This study aims to determine the frequency bands associated with Alzheimer’s disease in EEG data obtained from multiple channels and to accelerate the detection methods. An accurate classification that requires little computation is the primary goal. Results: EEG recordings of 48 individuals (24 AD and 24 healthy controls (HC)) obtained from Florida State University were divided into Alpha, Beta, Delta, Gamma, and Theta frequency bands; scalograms and spectrograms were generated for each frequency band. The effectiveness of these bands was evaluated using the MobileNetV2 architecture. The results showed that Delta and Beta frequency bands were the most significant for Alzheimer’s detection. By analyzing the features obtained from the Delta and Beta bands using the MobileNetV2 model integrated with the Dual-Attention Mechanism, it was determined that the attention mechanisms improved model performance by 2%. In addition, the use of an SVM classifier with hyperparameters optimized via Optuna resulted in approximately 3% performance improvement, suggesting that hyperparameter tuning may contribute positively to classification accuracy. Furthermore, combining features obtained from these frequency bands increased the detection performance when evaluated with larger datasets. Conclusions: The study demonstrates the potential of frequency band-based analyses and feature fusion methods to increase the accuracy and efficiency of Alzheimer’s diagnosis using EEG data. The results are promising; however, they should be interpreted with caution regarding their generalizability. Full article

Background: Alzheimer’s disease (AD) is largely linked with oxidative stress, the accumulation of amyloid-β plaques, and hyperphosphorylated τ-protein aggregation. Alterations in dopaminergic and serotonergic neurotransmission have also been implicated in various AD-related symptoms. Methods: To explore new therapeutic agents, a series of bicyclic and tricyclic thieno-oxazepine derivatives were synthesized as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The resultant compounds were purified via HPLC and characterized using spectral analysis techniques. Histopathological examinations, other antioxidants, and anti-inflammatory biomarkers were evaluated, and in silico ADMET calculations were performed for synthetic hybrids. Molecular docking was utilized to validate the new drugs’ binding mechanisms. Results: The most powerful AChE inhibitors were 14 and 16, with respective values of IC₅₀ equal to 0.39 and 0.76 µM. Derivative 15 demonstrated remarkable BChE-inhibitory efficacy, on par with tacrine, with IC₅₀ values of 0.70 µM. Hybrids 13 and 15 showed greater selectivity towards BChE, despite substantial inhibition of AChE. Compounds 13 and 15 reduced escape latency and raised residence time, with almost equal activity to donepezil. Conclusions: According to these findings, the designed hybrids constitute multipotent lead compounds that could be used in the creation of novel anti-AD medications. Full article

Background and Objectives: Over the past few years, there has been a significant shift in focus from developing better diagnostic tools to detecting Alzheimer’s disease (AD) earlier and initiating treatment interventions. This review will explore four main objectives: (a) the role of biomarkers in enhancing the diagnostic accuracy of AD, highlighting the major strides that have been made in recent years; (b) the role of neuropsychological testing in identifying biomarkers of AD, including the relationship between cognitive performance and neuroimaging biomarkers; (c) the amyloid hypothesis and possible molecular mechanisms of AD; and (d) the innovative AD therapeutics and the challenges and limitations of AD research. Materials and Methods: We have searched PubMed and Scopus databases for peer-reviewed research articles published in English (preclinical and clinical studies as well as relevant reviews and meta-analyses) investigating the molecular mechanisms, biomarkers, and treatments of AD. Results: Genome-wide association studies (GWASs) discovered 37 loci associated with AD risk. Core 1 biomarkers (α-amyloid Aβ42, phosphorylated tau, and amyloid PET) detect early AD phases, identifying both symptomatic and asymptomatic individuals, while core 2 biomarkers inform the short-term progression risk in individuals without symptoms. The recurrent failures of Aβ-targeted clinical studies undermine the amyloid cascade hypothesis and the objectives of AD medication development. The molecular mechanisms of AD include the accumulation of amyloid plaques and tau protein, vascular dysfunction, neuroinflammation, oxidative stress, and lipid metabolism dysregulation. Significant advancements in drug delivery technologies, such as focused Low-Ultrasound Stem, T cells, exosomes, nanoparticles, transferin, nicotinic and acetylcholine receptors, and glutathione transporters, are aimed at overcoming the BBB to enhance treatment efficacy for AD. Aducanumab and Lecanemab are IgG1 monoclonal antibodies that retard the progression of AD. BACE inhibitors have been explored as a therapeutic strategy for AD. Gene therapies targeting APOE using the CRISPR/Cas9 genome-editing system are another therapeutic avenue. Conclusions: Classic neurodegenerative biomarkers have emerged as powerful tools for enhancing the diagnostic accuracy of AD. Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. Novel monoclonal antibodies may halt the AD course. Advances in delivery systems across the BBB are promising for the efficacy of AD treatments. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and neuronal dysfunction. It is driven by the accumulation of amyloid-beta (Aβ) plaques, Tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. Resveratrol (RSV) is a natural polyphenolic compound found in grapes, berries, and red wine that has garnered attention for its potential neuroprotective properties in combating AD. The neuroprotective effects of RSV are mediated through the activation of sirtuins (SIRT1), inhibition of Aβ aggregation, modulation of Tau protein phosphorylation, and the attenuation of oxidative stress and inflammatory responses. RSV also enhances mitochondrial function and promotes autophagy, which are important processes for maintaining neuronal health. Preclinical studies have demonstrated its efficacy in reducing Aβ burden, improving cognitive performance, and mitigating synaptic damage; however, challenges such as poor bioavailability, rapid metabolism, and limited blood–brain barrier penetration restrict its clinical applicability. Recent technological advances and selected modifications are being explored to overcome these limitations and enhance its therapeutic efficacy. This review summarizes the multifaceted neuroprotective mechanisms of RSV, the synergistic potential of natural compounds in enhancing neuroprotection, and the advancements in formulation strategies aimed at mitigating AD pathology. Leveraging the therapeutic potential of natural compounds represents a compelling paradigm shift for AD management, paving the way for future clinical applications. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier dysfunction, oxidative stress (OS), and neuroinflammation. Current treatments provide symptomatic relief, but do not halt the disease’s progression. OS plays a crucial role in AD pathogenesis by promoting Aβ accumulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the antioxidant response, influencing genes involved in OS mitigation, mitochondrial function, and inflammation. Dysregulation of NRF2 is implicated in AD, making it a promising therapeutic target. Emerging evidence suggests that adherence to a Mediterranean diet (MD), which is particularly rich in polyphenols from extra virgin olive oil (EVOO), is associated with improved cognitive function and a reduced risk of mild cognitive impairment. Polyphenols can activate NRF2, enhancing endogenous antioxidant defenses. This study employs a computational approach to explore the potential of bioactive compounds in EVOO to modulate NRF2-related pathways in AD. We analyzed transcriptomic data from AD and EVOO-treated samples to identify NRF2-associated genes, and used chemical structure-based analysis to compare EVOO’s bioactive compounds with known NRF2 activators. Enrichment analysis was performed to identify common biological functions between NRF2-, EVOO-, and AD-related pathways. Our findings highlight important factors and biological functions that provide new insight into the molecular mechanisms through which EVOO consumption might influence cellular pathways associated with AD via modulation of the NRF2 pathway. The presented approach provides a different perspective in the discovery of compounds that may contribute to neuroprotective mechanisms in the context of AD. Full article