Search Results (56)

While Alzheimer’s disease (AD) is primarily considered a disorder of protein aggregation, converging evidence from clinical, neuropathological, and mechanistic studies strongly supports the notion that brain endothelial dysfunction is a primary and early event in AD pathogenesis. Brain endothelial pathways are among the most differentially expressed in human AD brains. Brain endothelial alterations precede amyloid deposition and cognitive deficits in experimental AD models and closely parallel the degree of neuronal loss in human AD brains. Despite growing evidence to support brain endothelial contributions to neurodegeneration, studies examining the potential of the brain endothelium as a druggable target in AD have been scarce. Further, there has been a relative paucity of validated fluid biomarkers that can reliably measure brain endothelial injury in AD, independently of overt vascular disease or disruption to other cerebrovascular constituents. In this perspective, we propose a brain endothelial glycocalyx-centric model of AD in which brain endothelial dysfunction, driven predominantly by non-enzymatic glycation and carbonyl stress, acts as a key upstream regulator of aberrant protein trafficking, blood–brain barrier instability, and dysregulated neuro-immune cascades. Further, recent evidence suggests the presence of direct interactions of the brain endothelium with key pathways involved in neuronal survival and synaptic signaling, highlighting potential direct contributions of brain endothelial disturbances to cognitive impairment. Within this framework, we identify several brain endothelial axes, including reduction in carbonyl stress, improved glycation-dependent signaling, attenuation of advanced glycation end-product (AGE)-mediated toxicity, and enhanced endothelial glycocalyx stability and resilience as potential therapeutic approaches in AD. Modulating brain endothelial glycation has potential as a novel therapeutic strategy in AD which may complement other disease-modifying treatments, particularly in the earliest preclinical stages. In conclusion, this framework positions the brain endothelium as a mechanistic hub linking metabolic stress to aberrant protein aggregation and neurodegeneration in AD with potential therapeutic implications in AD and other neurodegenerative disorders. Full article

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide, characterized by progressive cognitive decline, memory impairment, and neuronal loss. The pathological hallmarks of AD include extracellular accumulation of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic degeneration. Current symptomatic therapies provide modest clinical benefits, while recently approved amyloid-targeting monoclonal antibodies, such as lecanemab and donanemab, can slow decline in selected early-stage AD patients but do not cure the disease and are associated with safety, access, and cost concerns. This narrative review summarizes mechanistic evidence from in vitro and in vivo studies and distinguishes preclinical promise from validated clinical utility. Phytochemicals, including polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids, demonstrate neuroprotective effects through antioxidant activity, anti-inflammatory modulation, inhibition of amyloid aggregation, regulation of tau phosphorylation, and support of mitochondria and synapses. Evidence from experimental models suggests that several phytochemicals may help slow AD pathology and improve cognitive function, but clinical translation remains limited due to poor bioavailability, inadequate blood–brain barrier (BBB) penetration, and a lack of large-scale clinical trials. This review highlights critical research gaps and emerging strategies to facilitate phytochemical-based preventive and therapeutic approaches in AD. Full article

Accumulation of aggregated amyloid beta (Aβ) species is a defining pathological hallmark of Alzheimer’s disease and is associated with extensive neuronal structural abnormalities. Mild cognitive impairment (MCI), a transitional stage between normal aging and the onset of dementia, is thought to represent an early phase of this pathological continuum. Studies at the cellular level suggest that the conditions impair the maintenance of established neuronal processes/networks and restrict their capacity for elongation or re-elongation. They may also attenuate the activation and process extension of quiescent neural progenitor or stem-like cells. These early cellular changes precede overt neurodegeneration in neural tissue and are likely to contribute to cognitive decline. They highlight the importance of in vitro models for identifying molecular targets involved in recovery from disease. In this study, we investigated the effects of aggregated Aβ (25–35) on neuronal process elongation and associated intracellular events in the N1E-115 cell line, a widely used model of neuronal differentiation. Addition of aggregated Aβ to cultured N1E-115 cells attenuated process elongation in a concentration-dependent manner. This morphological impairment was accompanied by decreased expression of neuronal differentiation markers. In contrast, at the half-maximal inhibitory concentration for process elongation, long-term cultured cells did not exhibit apparent process retraction or degenerative morphology. This mild but progressive impairment, without extensive cell death, is consistent with the cellular features of early-stage conditions rather than advanced Alzheimer’s pathologies. Similar results were observed in primary cortical neurons. Aβ also decreased the level of GTP-bound Ras and phosphorylation of the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Furthermore, treatment with hesperetin, a bioactive flavonoid compound, recovered the Aβ-induced inhibition of neuronal process elongation. Hesperetin also restored Ras and MAPK/ERK states, suggesting that its effects are associated, at least in part, with modulation of signaling through Ras and MAPK/ERK. Our findings suggest that hesperetin may serve as a useful molecular probe for modulating early cellular responses associated with Alzheimer’s disease-related pathology. This in vitro model might serve as a useful platform for investigating the molecular target candidates involved in recovery from nervous system disorders. Full article

The intracellular accumulation of amyloid beta 42 (iAβ42) has been proposed as an early pathological indicator of familial Alzheimer’s disease (FAD). DJ-1 is a multifunctional protein sensitive to oxidative stress (OS) that has been associated with neurodegeneration; however, its role in iAβ42 pathology is unclear. In this study, we examined whether oxidized (sulfonic) DJ-1 (Cys¹⁰⁶-SO₃H) drives iAβ42 accumulation using postmortem brain samples and in vitro 3D iPSC-derived cerebral organoids (COs) or 2D induced pluripotent stem cells (iPSC)-derived ChLNs (cholinergic-like neurons) models from a PSEN1 E280A patient and a healthy volunteer (as a control sample). Post-mortem analyses of the temporal and frontal cortices and hippocampus from FAD PSEN1 E280A patients revealed strong intracellular co-localization of sulfonic DJ-1 and iAβ42, which was absent in control samples. To validate these findings, we generated COs from an iPSC PSEN1 E280A FAD patient and a healthy donor. In these organoids, we observed the co-localization of oxidized DJ-1 and Aβ42 in the absence of extracellular fibrils or plaques, as confirmed by BTA-1 staining. To further support these observations, 2D iPSC PSEN1 E280A-derived ChLNs cultures showed that intracellular Aβ42 accumulates progressively in direct correlation with increasing DJ-1 oxidation, as demonstrated by immunofluorescence microscopy and Western blotting analysis. These results indicate that DJ-1 oxidation accompanies the earliest intracellular stages of Aβ42 pathology. Furthermore, complementary in silico molecular docking analysis revealed a higher affinity between Aβ42 and oxidized sulfonic DJ-1 (DJ-1 Cys¹⁰⁶-SO₃H) compared to sulfenic (DJ-1 Cys¹⁰⁶-SOH) or sulfinic acid (DJ-1 Cys¹⁰⁶-SO₂H) forms. Likewise, ELISA tests and seeding assays confirmed that oxidized DJ-1 binds to and decelerates Aβ42 aggregation kinetics. Together, our results identify DJ-1 oxidation as a critical molecular event in the accumulation of iAβ42 in FAD. These findings suggest that oxidized DJ-1 represents not only a potential early biomarker of intracellular pathology but also a pharmacological target. Preventing the oxidation of DJ-1 or its pathological aggregation could provide new biomarkers and therapeutic strategies for reducing the intracellular accumulation of Aβ42 and neurodegeneration in FAD. Full article

Alzheimer’s disease is driven by converging pathological processes, including amyloid-β accumulation, tau dysfunction, synaptic failure, and chronic neuroinflammation, which emerge decades before clinical onset. Growing evidence supports the concept that early, upstream neuroprotective interventions may meaningfully alter disease trajectory in both sporadic and familial AD. Taurine, an endogenously abundant and clinically safe neuromodulator, has re-emerged as a promising multi-target regulator of AD-relevant pathways. Accumulating mechanistic data indicate that taurine modulates Aβ aggregation, attenuates oxidative and endoplasmic reticulum stress, preserves mitochondrial homeostasis, suppresses neuroinflammatory signaling, and stabilizes synaptic function, positioning it as a promising upstream intervention strategy in AD. This review synthesizes current evidence supporting taurine’s pleiotropic neuroprotective actions and discusses its translational potential as an early-stage, low-risk intervention to delay or prevent AD progression. Full article

Reliable and disease-specific blood biomarkers are critically needed for Alzheimer’s disease (AD), particularly in early stages when interventions are most effective. Although phosphorylated tau and neurofilament light chain (NfL) are widely used, their diagnostic specificity has been reported to decrease in elderly populations with multimorbidities. Syndecan-3 (SDC3), a heparan sulfate proteoglycan implicated in amyloid and tau aggregation, has recently emerged as a mechanistically relevant biomarker candidate. In this clinically realistic cohort study, we examined 46 participants, including 23 clinically diagnosed AD patients and 23 age-matched non-AD individuals with psychiatric and/or metabolic comorbidities. SDC3 expression was quantified in peripheral blood mononuclear cells (PBMCs), while soluble SDC3 and NfL were measured in plasma. Both PBMC-expressed and plasma SDC3 levels were elevated in AD compared with non-AD participants and showed a strong intercorrelation, whereas plasma NfL was likewise increased in AD. Individually, PBMC-SDC3, plasma SDC3, and NfL demonstrated moderate discriminatory performance. However, multivariable models integrating SDC3 (PBMC or plasma), NfL, and age achieved substantially improved discrimination (AUC > 0.8). SDC3 did not correlate with NfL, consistent with a biological signal distinct from neuroaxonal injury and reflective of peripheral immune–metabolic remodeling. Together, these findings identify SDC3 as a blood-based biomarker associated with systemic immune remodeling that complements established neuronal markers in a clinically realistic AD versus non-AD comparison. While exploratory, this study supports further investigation of SDC3 within integrated, multi-domain biomarker strategies in larger and independent cohorts. Full article

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR), with rarer forms occurring less frequently. AL amyloidosis arises from plasma cell-derived light chains and typically follows an aggressive clinical course, whereas ATTR amyloidosis results from misfolded wild-type or variant transthyretin and progresses more indolently. Extracellular vesicles (EVs) have recently been recognized as mediators of amyloid propagation, inflammation, and myocardial remodeling, particularly at later stages of disease. Despite growing evidence, no comprehensive reviews have focused on this relationship. We conducted a structured narrative review (PubMed and Scopus, 2020–2025) following Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines to synthesize emerging data. EVs act as scaffolds for transthyretin and serum amyloid A aggregation and carry disease-specific protein and RNA cargo detectable in blood and urine. Experimental models also demonstrate EV-mediated transport of serum amyloid A under conditions of cardiac stress, representing a reactive amyloidogenic pathway rather than a common cause of human cardiac amyloidosis. Preclinical studies show regenerative and anti-fibrotic effects of stem-cell-derived EVs, and early clinical trials demonstrate the feasibility of EV-based cardiac therapy. While methodological and translational challenges persist, EVs represent promising diagnostic and therapeutic tools that could transform the precision management of cardiac amyloidosis. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood–brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved. Full article

Alzheimer’s disease (AD) affects over 55 million individuals worldwide, yet no transformative disease-modifying therapies exist. Mathematical modelling provides a powerful framework to elucidate complex disease mechanisms, predict therapeutic outcomes, and enable precision medicine—capabilities urgently needed where multiscale spatiotemporal processes defy experimental analysis alone. We developed a mechanistic spatiotemporal model coupling four AD hallmarks: β-amyloid (Aβ) accumulation, T-protein (T-p) aggregation, neuroinflammation and electrical conductivity decline. Formulated as non-linear partial differential equations (p.d.es) on a 3-dimensional biological interpretation of non-linear terms (the ellipsoidal brain domain with biologically grounded parameters), the model was solved using eigenfunction expansion, Fourier analysis and numerical methods. Therapeutic interventions were simulated through mechanistically motivated parameter modifications and validated against longitudinal biomarker data from major cohort studies. Simulations reveal Aβ-initiated spatiotemporal cascades originating in the hippocampus and spreading radially at 0.15–0.20 cm/year, with T-pathology emerging after 2–3 years. Conductivity decline accelerates upon T-onset (year 5–7), reflecting the transition to symptomatic disease. Multimodal intervention at early symptomatic stages reduces peak Aβ by 36% and inflammation by 52% and preserves 41% more conductivity than untreated controls. Sensitivity analysis identifies Aβ production and inflammatory regulation as critical therapeutic targets, with dose–response curves demonstrating linear efficacy relationships. This biologically grounded framework explicitly links molecular pathology to functional decline, enabling patient-specific trajectory prediction through parameter calibration. The model establishes a foundation for precision medicine applications including individualized prognosis, optimal treatment timing and virtual clinical trial design, advancing quantitative systems biology of neurodegeneration. Full article

Background/Objectives: Alzheimer’s disease (AD) exhibits clinical and biological variability. This study aimed to identify MRI-defined subtypes reflecting distinct biological pathways of neurodegeneration and cognitive decline. Methods: We applied principal component analysis followed by k-means clustering (k = 3) on volumetric MRI data from 924 participants and validated clusters using cerebrospinal fluid (CSF) biomarkers (Aβ₄₂, total tau, p-tau, CTRED, MAPres, glucose, CTWHITE). Results: Three major phenotypes emerged: (1) a tau/vascular limbic subtype with pronounced hippocampal and amygdala atrophy and elevated tau and CTRED levels; (2) a volume-preserved, low-amyloid subtype consistent with early-stage or cognitively resilient AD; and (3) a diffuse-atrophy subtype with high amyloid and tau burden and ventriculomegaly. Comparative analysis revealed progressive biological shifts from amyloid accumulation to tau aggregation and vascular compromise across these clusters. Conclusions: MRI-based clustering validated by CSF biomarkers delineates biologically meaningful AD endophenotypes. The results suggest a gradual cognitive decline driven by amyloid–tau–vascular interactions, supporting multimodal phenotyping as a practical approach for precision staging and intervention. Full article

Alzheimer’s disease (AD), the leading cause of dementia, remains poorly understood despite decades of intensive research, which continues to hinder the development of effective treatments. As a complex multifactorial disorder, AD lacks a cure to halt the progressive neurodegeneration, and the precise mechanisms underlying its onset and progression remain elusive, limiting therapeutic options. Due to the challenges of studying neuronal cells in vivo, technologies such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) and human-induced pluripotent stem cells (hiPSCs) are key for identifying therapeutic targets, although they face technical and ethical hurdles in their early stages. CRISPR/Cas9 and hiPSCs are promising for disease modeling and therapy, but off-target effects and the complexity of gene editing in the brain limit their use. CRISPR technology enables specific genetic modifications in key AD-related genes, such as APP, PSEN1, PSEN2, and APOE, providing valuable insights into disease mechanisms. iPSC-derived neurons, astrocytes, microglia, and 3D organoids can recapitulate key aspects of human AD pathology, but they do not fully replicate the complexity of the human brain, limiting clinical applicability. These technologies advance studies of amyloid processing, tau aggregation, neuroinflammation, and oxidative stress, yet translating them into clinical therapies remains challenging. Despite the promise of CRISPR/Cas9 and iPSCs for precision medicine, gaps in knowledge about their long-term safety and efficacy must be addressed before clinical implementation. Full article

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that often begins decades before clinical symptoms manifest. Early detection remains critical for effective intervention, particularly in younger adults, where biomarker deviations may signal pre-symptomatic risk. This research presents a computational modeling framework to predict cognitive impairment progression and stratify individuals into risk zones based on age-specific biomarker thresholds. Methods: The model integrates sigmoid-based data generation to simulate non-linear biomarker trajectories reflective of real-world disease progression. Core biomarkers—including cerebrospinal fluid (CSF) amyloid-beta 42 (A${\beta }_{42}$), amyloid positron emission tomography (amyloid PET), cerebrospinal fluid Tau protein (CSF Tau), and magnetic resonance imaging with fluorodeoxyglucose positron emission tomography (MRI FDG-PET)—were analyzed simultaneously to compute the cognitive impairment (CI) score of instances, dynamically adjusted for age. Higher CSF A${\beta }_{42}$ levels consistently demonstrated a protective effect, while elevated amyloid PET and Tau levels increased cognitive risk. Age-specific CI thresholds prevented the overestimation of risk in younger individuals and the underestimation in older cohorts. To demonstrate its applicability, we applied the full four-stage framework—comprising data aggregation and cleaning, sigmoid-based synthetic biomarker simulation with descriptive analysis, parameter accumulation modeling, and correlation-driven CI classification—on a curated dataset of 307 instances (ages 10–110) from Kaggle, the Alzheimer’s Disease Neuroimaging Initiative (ANDI), and the Open Access Series of Imaging Studies (OASIS) to evaluate age-specific stratification of preclinical AD risk. Results: The study highlights the model’s potential to identify individuals in risk zones from a pool of 150 instances, enabling targeted early interventions. Furthermore, the framework supports retrospective disease trajectory analysis, offering clinicians insights into optimal intervention windows even after symptom onset. Conclusions: Future work aims to validate the model using longitudinal, inclusive, real-world datasets and expand its predictive capacity through machine learning techniques and integrating genetic and lifestyle factors. Ultimately, this research contributes to advancing precision medicine approaches in Alzheimer’s disease by providing a scalable computational tool for early risk assessment and intervention planning. Full article

Recently, it has been hypothesized that alpha-synuclein protein strain morphology may be associated with clinical subtypes of alpha-synucleinopathies, like Parkinson’s disease and multiple system atrophy. However, direct evidence is lacking due to the caveat of conformation-specific characterization of protein strain morphology. Here we present a new cell model based in vitro method to explore various alpha-synuclein (αsyn) aggregate morphotypes. We performed a spectroscopic investigation of the HEK293 cell model, transfected with human wildtype-αsyn and A53T-αsyn variants, using the amyloid fibril-specific heptameric luminescent oligomeric thiophene h-FTAA. The spectral profile of h-FTAA binding to aggregates displayed a blue-shifted spectrum with a fluorescence decay time longer than in PBS, suggesting a hydrophobic binding site. In vitro spectroscopic binding characterization of h-FTAA with αsyn pre-formed fibrils suggested a binding dissociation constant K_d < 100 nM. The cells expressing the A53T-αsyn and human wildtype-αsyn were exposed to recombinant pre-formed fibrils of human αsyn. The ensuing intracellular aggregates were stained with h-FTAA followed by an evaluation of the spectral features and fluorescence lifetime of intracellular αsyn/h-FTAA, in order to characterize aggregate morphotypes. This study exemplifies the use of cell culture together with conformation-specific ligands to characterize strain morphology by investigating the spectral profiles and fluorescence lifetime of h-FTAA, based upon its binding to a certain αsyn aggregate. This study paves the way for toxicity studies of different αsyn strains in vitro and in vivo. Accurate differentiation of specific alpha-synucleinopathies is still limited to advanced disease stages. However, early subtype-specific diagnosis is of the utmost importance for prognosis and treatment response. The potential association of αsyn aggregates morphotypes detected in biopsies or fluids to disease phenotypes would allow for subtype-specific diagnosis in subclinical disease stage and potentially reveal new subtype-specific treatment targets. Notably, the method may be applied to the entire spectrum of neurodegenerative diseases by using a combination of conformation-specific ligands in a physicochemical environment together with other types of polymorphic amyloid variants and assess the conformation-specific features of various protein pathologies. Full article

Neurodegenerative diseases (NDDs) are a diverse group of neurological disorders characterized by alterations in the structure and function of the central nervous system. Alzheimer’s disease (AD), characterized by impaired memory and cognitive abilities, is the most prevalent type of senile dementia. Loss of synapses, intracellular aggregation of hyperphosphorylated tau protein, and extracellular amyloid-β peptide (Aβ) plaques are the hallmarks of AD. MicroRNAs (miRNAs/miRs) are single-stranded ribonucleic acid (RNA) molecules that bind to the 3′ and 5′ untranslated regions of target genes to cause post-transcriptional gene silencing. The brain expresses over 70% of all experimentally detected miRNAs, and these miRNAs are crucial for synaptic function and particular signals during memory formation. Increasing evidence suggests that miRNAs play a role in AD pathogenesis and we provide an overview of the role of miRNAs in synapse formation, Aβ synthesis, tau protein accumulation, and brain-derived neurotrophic factor-associated AD pathogenesis. We further summarize and discuss the role of miRNAs as potential therapeutic targets and biomarkers for AD detection and differentiation between early- and late-stage AD, based on recent research. In conclusion, altered expression of miRNAs in the brain and peripheral circulation demonstrates their potential as biomarkers and therapeutic targets in AD. Full article

Amyloid β peptide (Aβ) aggregation and deposition are considered the main causes of Alzheimer’s disease. In a previous study, we demonstrated that anionic Zn-phthalocyanine (ZnPc) can interact with the Aβ peptide and inhibit the fibril-formation process. However, due to the inability of anionic ZnPc to cross the intact blood–brain barrier, we decided to explore the interaction of cationic methylated Zn-phthalocyanine (cZnPc) with the peptide. Using a ThT fluorescence assay, we observed that cZnPc dose-dependently and time-dependently inhibited Aβ_1-42 fibril levels under in vitro fibril-formation conditions. Electron microscopy revealed that it caused Aβ_1-42 peptides to form small aggregates. Western blotting and dot immunoblot oligomer experiments demonstrated that cZnPc increased rather than decreased the levels of oligomers from the very early stages of incubation. A binding assay confirmed that cZnPc could bind with the peptide. Docking simulations indicated that the oligomer species of Aβ_1-42 had a higher ability to interact with cZnPc. ANS fluorescence assay results indicated that cZnPc did not affect the hydrophobicity of the peptide. However, cZnPc significantly increased intrinsic tyrosine fluorescence of the peptide after 8 h of incubation in fibril-formation conditions. Importantly, cell culture experiments demonstrated that cZnPc did not exhibit any toxicity up to a concentration of 10 µM. Instead, it protected a neuronal cell line from Aβ_1-42-induced toxicity. Thus, our results suggest that cZnPc can affect the aggregation process of Aβ_1-42, rendering it non-toxic, which could be crucial for the therapy of Alzheimer’s disease. Full article