Exosomes represent a promising class of naturally produced nanoparticles that exist at the nanoscale and carry a negative surface charge under physiological conditions. These tiny membranebound vesicles are released by cells throughout the body and function as biological messengers, transporting various molecular cargos between cells and facilitating critical cell-to-cell communication pathways. Existing therapies for neurodegenerative disorders face two critical barriers: they cannot precisely target the affected brain areas, and the blood-brain barrier blocks most potential treatments from entering the brain. Exosomes offer a promising solution to these challenges. Unlike most synthetic drug delivery systems that struggle to penetrate the brain's protective barrier, these naturally derived nanocarriers exhibit an inherent capacity to traverse the blood-brain barrier. This unique property, combined with their capacity for efficient intracellular delivery of therapeutic payloads, positions exosomes as an exciting platform for transporting pharmaceutical agents to the affected neural tissues. Through strategic engineering and modification, these vesicles can be transformed into highly precise delivery vehicles capable of targeting specific organs, tissues, or even individual cell types. This review explores the therapeutic potential and drug delivery applications of exosomes in the management of major neurodegenerative disorders. This review provides an in-depth examination of exosome biogenesis, current isolation methodologies, and surface engineering strategies, while critically evaluating the strengths and limitations of each approach. In addition, this review summarizes the current preclinical models and provides an overview of ongoing clinical trials investigating exosome-based therapies for neurological disorders.
Neurodegenerative dementias, including Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, and related tauopathies, are traditionally defined by protein aggregation, neuronal dysfunction, synaptic loss, and glial-mediated neuroinflammation. However, emerging evidence indicates that adaptive immunity may also contribute to disease heterogeneity and progression. These disorders should not be considered classical autoimmune diseases, but they may display autoimmune-like signatures, including neural antigen-specific T cell responses, clonal expansion of T cells in blood or cerebrospinal fluid, CNS infiltration of adaptive immune cells, and brain-targeting autoantibodies. Recent studies have linked α-synuclein-specific T cell reactivity to early Parkinson's disease, identified clonally expanded CD8+ T cells in Alzheimer's disease cerebrospinal fluid, and provided direct evidence of adaptive immune involvement in Lewy body dementia, including altered peripheral immunophenotypes and CD4+ T cell-associated neurodegenerative mechanisms. Experimental tauopathy models further show that microglia-mediated T cell infiltration can drive neurodegeneration. Humoral autoreactivity and progression-associated immune changes further suggest that adaptive immune profiles may help define biologically distinct dementia subgroups. In this mini review, we summarize evidence connecting peripheral immune activation, intrathecal adaptive immune remodeling, and CNS pathology in neurodegenerative dementias. We also discuss how longitudinal blood-CSF profiling, single-cell/TCR/BCR sequencing, autoantibody profiling, and mechanistic validation may clarify whether these immune signatures are pathogenic, compensatory, or bystander responses.
Bioactive compounds from traditional Chinese medicine (TCM) have shown therapeutic potential in neurodegenerative diseases (NDDs), particularly through the regulation of mitochondrial function. Recent studies indicate that encapsulating these TCM bioactive compounds in nanodelivery systems significantly enhances their bioavailability, improves their ability to target the central nervous system, and offers more precise drug delivery. This review aims to synthesize current evidence on how TCM bioactive compounds modulate mitochondria-related pathological nodes in NDDs and discuss how nanodelivery systems can be rationally engineered for blood-brain barrier (BBB) traversal, neuronal uptake, and mitochondrial or mitochondrial dysfunction-responsive delivery. This is a structured narrative review. Relevant literature on TCM bioactive compounds, mitochondrial dysfunction, and nanodelivery systems for NDDs was retrieved from PubMed, Web of Science, and Scopus through April 2026. After applying predefined inclusion criteria, studies published between 2014 and 2025 were selected for analysis. The emphasis was placed on mechanistic studies, representative nanoformulations, and recent translational evidence. Current evidence indicates that bioactive compounds from traditional Chinese medicine, particularly polyphenols, alkaloids, flavonoids, saponins, and terpenoids, converge on several shared mitochondrial pathological nodes in neurodegenerative diseases, including oxidative stress, impaired bioenergetics, disrupted mitochondrial dynamics, defective mitophagy, and mitochondria-mediated apoptosis. Nanodelivery systems consistently improve the physicochemical properties, pharmacokinetic stability, blood-brain barrier transport, and intracellular exposure of these compounds, thereby enhancing their therapeutic potential. Mechanistically, rational integration of disease-responsive nanocarriers with mitochondria-regulating compounds enables spatiotemporal modulation of mitochondrial function rather than merely increasing drug accumulation. However, current evidence remains predominantly preclinical, with most formulations achieving brain targeting rather than verified mitochondrial subcellular targeting. Standardized evaluation of multistage BBB-neuron-mitochondria delivery efficiency, long-term safety, and translational performance is still lacking. Mitochondrial dysfunction-oriented nanodelivery of TCM bioactive compounds represents a promising strategy for NDD intervention. Future progress depends on more rigorous quality control from the herbal materials to the final nanoformulations, improved pharmacokinetic and safety evaluations, better disease-relevant animal models, and regulatory science frameworks tailored for botanical nanomedicines.
The 'European Prospective Investigation into Cancer and Nutrition' cohort (EPIC) is a prospective study including ~ 520,000 participants recruited across Europe (1991-2000) with in-depth baseline data on nutritional, lifestyle, medical, and anthropometric variables, and baseline blood samples. Here we introduce EPIC4ND, a case-cohort study within EPIC designed to identify biomarkers predicting a future onset of dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). EPIC4ND comprises 6415 initially non-diseased participants (aged 35-80 years, mean age at baseline: 54 ± 9, 64% women) including 1899 incident cases with up to 30 years of follow-up and data on at least one omics domain available from pre-disease blood samples. EPIC4ND includes 4604 subcohort members (4441 non-cases and 163 incident cases) and 1811 additional incident cases ascertained from the broader EPIC cohort. Among the incident cases, there are 1190 dementia cases (818 AD), 610 PD cases, and 199 ALS cases. Additionally, 72 prevalent PD cases and 118 incident Parkinsonism cases are available for comparison. Molecular data generated encompass proteomics, genome-wide DNA methylation, and SNP genotyping with 4127 EPIC4ND participants (including 1635 incident cases) having data on all three domains. Smaller studies include data on metals, metabolites, and environmental chemicals, while ongoing efforts focus on ultrasensitive targeted biomarker measurements and small RNA sequencing. Genome-wide association studies and analyses of epidemiological risk factors validate the dataset by confirming many known risk factors. Leveraging these extensive pre-disease multi-layered omics data offers a unique opportunity to identify biomarker signatures predicting neurodegenerative diseases and to explore their interplay with epidemiological risk factors.
Behavioral variant frontotemporal dementia is characterized by significant changes in personality and behavior with typical age of onset between the fifth and sixth decade of life. The following case study describes a 44-year-old female patient with a significant psychiatric history and distant mild traumatic brain injury who began to behaviorally decompensate in her mid-to-late 30s. She was referred for neuropsychological evaluation due to report of memory problems and progressive neuropsychiatric and neurobehavioral decline. Neuropsychological testing revealed diffuse cognitive impairment mediated by pronounced neurobehavioral executive dysfunction. Laboratory and genetic testing were unremarkable. Neuroimaging revealed statistically significant asymmetric hypometabolism in the bilateral frontotemporal region, more pronounced on the left. Taken together, results were suggestive of a primary underlying frontotemporal lobar degenerative process with secondary exacerbation due to chronic psychiatric distress. This case report highlights the importance of thorough differential diagnosis of a neurodegenerative process in a young adult with an overlay of longstanding psychiatric illness, especially when the etiology in question falls outside the typical age of onset.
Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, a key post-translational modification (PTM) regulating chromatin organization, RNA metabolism, and signaling. Recent studies reveal that PRMT-mediated methylation also modulates liquid-liquid phase separation (LLPS), which organizes membraneless condensates controlling transcription, stress response, and genome stability. Dysregulated PRMT activity disrupts condensate dynamics, contributing to cancer and neurodegenerative diseases. In cancer, PRMT1, PRMT5, and PRMT6 promote tumor progression via methylation-dependent condensates that enhance oncogenic transcription and stress resistance. In the nervous system, PRMT1, PRMT4, PRMT5, PRMT6, and PRMT8 regulate LLPS of proteins, linking aberrant methylation to ALS and Huntington's disease. This review highlights PRMTs as key modulators of phase separation and potential therapeutic targets in both oncology and neurodegeneration.
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Insulin resistance, a major component of metabolic syndrome (MetS), is involved in phosphorylated tau and beta amyloid buildup, linking MetS to neurodegenerative processes, e.g., Alzheimer's disease. One of the initial signs of neurodegeneration, in diseases such as Parkinson's and Alzheimer's, is olfactory dysfunction. Accordingly, in previous reports we found that high carbohydrate diet based on 30% sucrose in drinking water, increased visceral fat and insulin resistance, leading to an augment of oxidative stress and reduced brain energy metabolism, upregulating amyloidogenic genes (APP and BACE1) in hypothalamus and hippocampus. Thus, herein we comparatively evaluated the effect of sucrose induced MetS on episodic memory, olfaction, protein expression in amyloidogenic and insulin pathways, lipoperoxidation, antioxidant and BACE1 enzymatic activity between the hippocampus and olfactory bulb in male Wistar rats. Also, cellular structure of the olfactory bulb was analyzed. After 24 weeks of 30% sucrose consumption, we found preserved performance in a memory test; decreased hippocampal expression of APP and hyperactivation of the insulin pathway, low levels of lipoperoxidation, and high activity of antioxidant and BACE1 enzymes. Olfactory dysfunction was present in MetS rats, accompanied by morphological alterations in the olfactory bulb along with BACE1 increased activity. Thus, chronic high-sucrose consumption may prime the brain for neurodegenerative processes by modulating insulin signaling, oxidative stress homeostasis and amyloidogenic pathways in a region-dependent manner, with the olfactory system emerging as an early and sensitive target of metabolic dysfunction.
Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are now recognized as integral components of the proteostasis network that preserves cellular and tissue function across the lifespan. With aging, increasing oxidative load, metabolic imbalance, and Ca2⁺ dysregulation elevate the burden of misfolded proteins in the ER, leading to progressive UPR engagement. When ER stress is mild or transient, UPR signaling restores folding capacity, restrains translation, and enhances redox and degradative programs, thereby promoting cellular resilience. In contrast, persistent or repeatedly unresolved ER stress narrows this adaptive window and biases UPR outputs toward chronic inflammation, stable growth arrest, and cell loss processes that collectively drive inflammaging, stem/progenitor exhaustion, tissue degeneration, and vulnerability to neurodegenerative disease. This review synthesizes evidence that ER stress is not merely a correlation of aging but a mechanistic contributor to age-related decline, with senescence emerging as a major downstream fate in multiple tissues. It also highlights how context- and duration-dependent PERK signaling can be protective early, yet maladaptive when chronically engaged, shaping senescence programs and influencing neuronal survival and neurodegenerative disease progressions. Finally, this review discusses therapeutic opportunities and open questions centered on restoring adaptive PERK/ISR dynamics to support healthy aging.
Nucleophosmin1 (NPM1) proteins, initially recognized as central guardians of nucleolar architecture and function, have recently been redefined as pivotal hubs that integrate diverse forms of chronic cellular stress signaling. Although the roles of NPM1 have been extensively elucidated in tumor biology, its broad involvement in non-communicable chronic inflammatory diseases (NCDs) remains insufficiently and unsystematically summarized. Here, we highlight NPM1 as a key sensor of stress-induced nucleolar disassembly, nucleocytoplasmic translocation, and p53 stabilization. In pathological conditions such as myocardial ischemia, endothelial dysfunction, atherosclerosis, and chemotherapy-associated cardiotoxicity, NPM1 exhibits pronounced context dependence functioning either to initiate cytoprotective responses or to promote inflammation and apoptosis. In parallel, NPM1 plays a central role in maintaining genomic stability by sequestering, mobilizing, and regulating essential enzymes across multiple DNA damage repair pathways, including base excision repair (BER) and translesion synthesis (TLS). Dysregulation of these functions is closely linked to chronic pathological processes driven by metabolic stress, oxidative stress, and proteotoxicity. Collectively, available evidence suggests that NPM1, as a core node of the nucleolus-nucleoplasm signaling axis, may constitute a common molecular pathological basis underlying multiple chronic inflammatory diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders. A deeper dissection of its post-translational modifications, stress-dependent subcellular re-localization, and interactions with partner proteins is expected to provide a novel conceptual framework and therapeutic avenues for the development of NPM1-based targeted interventions. Accordingly, this review synthesizes the core molecular mechanisms of the NPM1 in the maintenance of cellular homeostasis, including regulating nucleolar stress, DNA damage repair, and inflammation, We place a particular emphasis on how these baseline pathways translate into distinct functional phenotypes within the pathological processes of chronic diseases, including cardiovascular, metabolic, and neurodegenerative disorders.
BackgroundRetinal structural and microvascular alterations detected by optical coherence tomography (OCT) and OCT angiography (OCTA) have emerged as promising biomarkers of Alzheimer's disease (AD). However, the extent to which retinal changes reflect cerebral neurodegenerative and vascular pathology and contribute to cognitive impairment remains incompletely characterized.ObjectiveTo investigate the relationships among retinal OCT/OCTA metrics, cerebral neuroimaging markers, and global cognitive performance in patients with AD.Methods115 AD and 101 cognitively unimpaired controls underwent OCT/OCTA imaging, 3.0T brain magnetic resonance imaging, and neuropsychological assessment. Retinal structural measures, including peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses, and retinal microvascular densities of the superficial vascular complex (SVC) and deep vascular complex were analyzed alongside white matter hyperintensity (WMH) volume, hippocampal volume, and cerebral small vessel disease (SVD) burden.ResultsCompared with controls, patients with AD exhibited significantly thinner pRNFL and GCIPL and lower SVC density (all p < 0.01). Retinal structural and microvascular alterations were associated with greater WMH burden, hippocampal atrophy, increased SVD burden, and lower Mini-Mental State Examination and Montreal Cognitive Assessment scores (all p < 0.05). Significant interactions were observed between GCIPL thickness and periventricular WMH volume in relation to cognitive performance. Mediation analyses demonstrated that WMH volume and SVD burden partially mediated the association between reduced SVC density and cognitive impairment.ConclusionsRetinal OCT/OCTA metrics are associated with cerebral neurodegenerative and vascular abnormalities and reflect cognitive dysfunction in AD, supporting their potential utility as accessible, noninvasive biomarkers for disease assessment and monitoring.
ObjectiveParkinson's disease (PD) is a progressive neurodegenerative disorder marked by motor and non-motor symptoms. While cholesterol metabolism has been implicated in PD pathogenesis, its role in long-term mortality remains unclear. The intention of this study was to evaluate if cholesterol parameters impact the 5-year all-cause mortality of PD patients.MethodsThis study has a retrospective cross-sectional design, including a total of 212 PD, patients which were grouped by treatment (DBS or BMT). Cognitive function, depressive symptoms, and motor status were assessed with standardized instruments. Cholesterol parameters (total cholesterol, LDL, HDL, TC/HDL ratio) were measured within ± 90 days of neuropsychological testing. Cox proportional hazards models and Kaplan-Meier analyses were used to examine associations with 5-year mortality.ResultsFive-year survival likelihood was 88.4% for DBS and 66.7% for BMT. However, cholesterol parameters emerged as non-significant predictors of mortality in the Cox regression model. Age occurred as the only significant predictor.ConclusionCholesterol levels do not appear to predict 5-year mortality in PD patients. Age was the strongest risk factor. Further studies are recommended to clarify cholesterol's role in PD progression and mortality.
Group VIA calcium-independent phospholipaseA2 (iPLA2β or PLA2G6) is a homeostatic enzyme involved in basal glycerophospholipid metabolism. The mutations in the PLA2G6 gene lead to heterogenous neurodegenerative disorders. Global PLA2G6 inactivation in iPLA2β-null mice exhibited liver fibrosis and intestinal atrophy when they reached an advanced age at 20-22 months old. Here, we analyzed the phenotypes of iPLA2β-null mice which happened to be exposed to natural pathogens in our animal facility. Compared with wild-type, male iPLA2β-null mice at 9-14 months of age exhibited reduced body, liver, and subcutaneous fat weights concomitant with decreased hepatic triacylglycerol and decreased expression of de novo lipogenesis genes. Hepatocytes from male mutants were sensitive to apoptosis induced by palmitic acid. Male but not female mutants displayed attenuation of hepatic lipid synthesis; however hepatic fibrosis was increased in mutants of both sexes. Hepatic apoptosis was also increased in mutants of both sexes, and they were susceptible to endotoxin-induced liver injury. Hence, global PLA2G6 inactivation combined with natural infection accelerates progression of chronic liver disease in both male and female mice with male-biased alteration of hepatocellular glycerolipid metabolism.
Metal-organic macrocycles provide a versatile platform for integrating multiple chemical functions within a single, well-defined architecture, yet their potential for regulating pathological protein aggregation remains largely unexplored. Here we report rationally designed metal-organic macrocycles that combine piano-stool ruthenium or iridium complexes with a photoactivatable bis(difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine (BOPHY)-based ligand to enable dual-mode modulation of amyloid-β (Aβ) aggregation associated with Alzheimer's disease. These macrocycles directly engage Aβ species through surface interactions and, upon light activation, induce oxidative modifications via singlet oxygen, collectively altering aggregation behavior and aggregate morphologies. As a result, they suppress the formation of toxic Aβ assemblies and attenuate Aβ-induced cytotoxicity. Overall, this work establishes metal-organic macrocycles as effective modulators of amyloidogenesis and provides a potential strategy for controlling complex protein aggregation processes in neurodegenerative diseases.
Primary angle-closure glaucoma (PACG) induces widespread central nervous system remodeling. However, the molecular, cellular, and neurochemical architectures driving macroscopic functional synchronization abnormalities in PACG remain unexplored. We employed a multiscale imaging-transcriptomics framework. Resting-state functional MRI was used to evaluate regional homogeneity (ReHo) in 44 PACG patients and 57 healthy controls. Voxel-wise ReHo alterations were spatially linked to whole-brain gene expression profiles from the Allen Human Brain Atlas, canonical cell-type-specific expression data, and multimodal PET neurotransmitter maps. PACG patients exhibited decreased ReHo in the primary visual cortex and compensatory increases across widespread subcortical and higher-order associative cortices. These macroscopic ReHo alterations significantly covaried with a specific transcriptional profile characterized by the upregulation of stress response and extracellular matrix remodeling pathways, alongside the downregulation of synaptic transmission. Cellular enrichment analysis revealed that these transcriptomic signatures were highly specifically localized to the neurovascular and glial axis (astrocytes, endothelial cells, and oligodendrocytes) rather than neuronal lineages. Furthermore, the ReHo abnormality map was significantly coupled with the spatial distribution of multiple neurotransmitters, particularly dopamine, gamma-aminobutyric acid, and serotonin receptors. This study provides multidimensional evidence that PACG-induced functional synchronization alterations are tightly constrained by underlying transcriptomic gradients, glial-vascular networks, and neurochemical architectures, reinforcing the conceptualization of PACG as a systemic central neurodegenerative disease.
Speech and voice changes affect up to 90% of people with Parkinson's disease (PD), a progressive neurodegenerative disorder affecting approximately 10 million people worldwide. Although continuous monitoring of disease severity is clinically important, most existing voice-based computational approaches focus on binary PD-versus-control classification and do not model longitudinal symptom progression. To address this gap, we propose a domain-adaptive transformer model, DAT-PD, for predicting continuous PD severity trajectories from real-world smartphone voice recordings. DAT-PD was developed using the public mPower dataset, comprising 58,247 voice recordings from 5,800 participants. The proposed pipeline included noise-aware acoustic preprocessing, extraction of extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS) features, a domain-adaptive attention mechanism to reduce cross-device and cross-environment variability and a longitudinal trajectory decoder. The model was trained, inferred, and evaluated using continuous MDS-UPDRS Part-II scores as the sole prediction target. Confounder-aware domain adaptation was incorporated to address demographic imbalance, including the age gap between the PD cohort and healthy controls. Robustness was further evaluated under harsh acoustic conditions with signal-to-noise ratios as low as 0 dB. On the held-out test set, DAT-PD achieved a mean absolute error (MAE) of 2.74 MDS-UPDRS units (95% CI: 2.44-3.01), root mean squared error (RMSE) of 3.61 (95% CI: 3.18-4.04), and R² of 0.93 (95% CI: 0.91-0.95), outperforming six state-of-the-art baseline models. eGeMAPS features substantially outperformed MFCC-only representations, reducing MAE from 5.21 to 2.74. SHAP-based explainability identified MFCC-2, Shimmer (APQ5) and Jitter as the most influential longitudinal voice biomarkers. The superior performance of DAT-PD suggests that domain-adaptive longitudinal modeling can effectively capture clinically meaningful voice-based severity trajectories in PD. The advantage of eGeMAPS over MFCC-only features is likely due to its ability to represent phonatory and prosodic characteristics relevant to PD dysarthria, including F0 dynamics, loudness contour, shimmer, jitter and spectral flux. By maintaining robustness under noisy real-world acoustic conditions, DAT-PD supports unsupervised home-based monitoring using standard smartphones. These findings align with the Bridge2AI-Voice research agenda and position DAT-PD as a clinically implementable, non-invasive tool for continuous PD severity assessment.
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. Attention deficits are common in patients with PD, and balance can be affected by sleep quality and depression. The auditory event-related potential (ERP) P300 tool is associated with attention and discrimination processes and is a sensitive indicator of attention. This study aimed to investigate the effects of balance, sleep quality, and depression on attention in individuals with PD using P300 latency. In this cross-sectional study, 28 individuals with PD and 27 healthy controls were assessed. Attention was measured using the auditory ERP P300, balance with the Berg Balance Scale (BBS), sleep quality with the Pittsburgh Sleep Quality Index (PSQI), and depression with the Beck Depression Inventory (BDI). Multiple linear regression analysis was used to examine the effects of these variables on P300 latency. Significant differences were found between the groups in terms of attention, balance, sleep quality, and depression (all P < 0.001). Regression analysis indicated that balance (B = -4.909, P = 0.001) and sleep quality (B = 12.704, P = 0.007) were significantly associated with P300 latency, whereas depression (B = 3.472, P = 0.084) was not. PD is associated with impaired attention, balance deficits, poor sleep quality, and increased depressive symptoms. The significant association between balance performance and sleep quality with attentional processing highlights their potential relevance in clinical assessment and management. The study was registered with Clinical Trials (NCT04687371 - https://clinicaltrials.gov/study/NCT04687371).
Rabbit models induced by a high-cholesterol diet can exhibit Alzheimer's disease (AD)-like neuropathological features, but susceptibility to diet-induced pathological alterations may vary with age and strain. This study aimed to investigate age-dependent susceptibility to high-cholesterol-diet-induced AD-like alterations in white-haired and black-eyed (WHBE) rabbits using a multimodal approach. Compared with the normal control group (NC), juvenile rabbits (2 months old) in the 2% high-cholesterol diet (CD) group showed disturbed plasma lipid and glucose metabolism, increased body weight, and reduced encephalization quotient (EQ). Neuropathologically, juvenile CD rabbits exhibited enhanced hippocampal Tau hyperphosphorylation and Aβ deposition. MRI demonstrated significant hippocampal atrophy and lateral ventricular enlargement, while 1H-MRS revealed significant reductions in hippocampal N-acetylaspartate/Cr, glutamate (Glu)/Cr, and glycerophosphocholine (GPC)+phosphocholine (PCH)/Cr ratios. In the overall cohort, Tau protein expression was negatively correlated with (Glu+Gln)/Cr (rho = -0.50, P = 0.0096) and positively correlated with (GPC+PCH)/Cr (rho = 0.42, P = 0.0167), although these correlations lost significance after FDR correction in subgroup analyses. Additionally, Aβ expression was negatively correlated with age in pooled WHBE rabbits (rho = -0.35, P = 0.0437), with no significant metabolite correlations observed after multiple testing correction. Multiple linear regression further confirmed a significant 'Diet×Age' interaction for both Tau and Aβ, indicating the pathological effect of high-cholesterol diet was most prominent in juvenile animals. These findings suggest that juvenile WHBE rabbits are more vulnerable to high-cholesterol-diet-induced AD-like changes. This study provides a multimodal reference for optimizing rabbit AD models and exploring age-related neurodegenerative vulnerability.
To critically integrate epidemiological, mechanistic, and clinical evidence linking systemic blood pressure dysregulation and diabetes mellitus with glaucomatous optic nerve injury, while distinguishing biological plausibility and association from demonstrated causality. PubMed/MEDLINE was searched from database inception through 30 June 2026 using three prespecified blocks covering blood pressure exposures, diabetes and candidate antidiabetic therapies, and glaucoma subtypes. Backward citation tracking and targeted journal and publisher searches identified additional and recently published studies. Owing to clinical and methodological heterogeneity, evidence was synthesised as a structured narrative review. Chronic hypertension may be associated with higher intraocular pressure, vascular remodelling, and impaired autoregulation, whereas systemic hypotension, nocturnal over-dipping, and blood pressure variability may reduce or destabilize ocular perfusion. Diabetes has plausible microvascular, metabolic, and neurodegenerative effects, but epidemiological findings are inconsistent and glycated haemoglobin does not consistently predict glaucoma progression. Evidence is strongest for primary open-angle and normal-tension glaucoma. Findings concerning metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors remain predominantly observational, genetic, translational, or preclinical. Systemic vascular and metabolic factors may modify optic nerve susceptibility but are not established independent causes or treatment targets. Intraocular pressure lowering remains the therapeutic cornerstone, and prospective glaucoma-specific intervention studies are needed before systemic treatment recommendations can be made.
Estrogen operates as a pleiotropic steroidal, neuroendocrine modulator to combat accelerated brain ageing and neurodegeneration by addressing a convergent inflammatory-metabolic trio. Estrogen receptor-dependent neural cellular signalling reduces TLR4-mediated immune priming and NF-κB activation, preventing NLRP3 inflammasome assembly and pro-inflammatory cytokine release. Concurrently, estrogen increases SIRT1 activity, restoring metabolic and epigenetic equilibrium while inhibiting HMGB1 acetylation, translocation, extracellular release, and activation of the stress-response pathway. Coordinated regulation of the TLR4-NFκB-NLRP3 and SIRT1-HMGB1 molecular triad reduces chronic neuroinflammation, preserves neuronal integrity, metabolic resilience, and slows persistent inflammation-driven brain ageing. This highlights estrogen and estrogen-based steroidal modulators as promising therapeutic candidates for reversing accelerated cognitive ageing and neurodegenerative disorders. However, a crucial research gap persists in the absence of a systems-level assessment of neurosteroids as a multi-target regulator of convergent innate immunological and metabolic signalling networks. The control of the TLR4-NFκB-NLRP3 inflammasome axis and the SIRT1-HMGB1 metabolic-epigenetic checkpoint has not been well studied as an interrelated, steroidal druggable trifecta driving brain homeostasis and neurodegeneration. These pathways are often studied in isolation, despite overwhelming evidence that their bidirectional interplay contributes to persistent neuroinflammation, immunometabolic dysfunction, and cellular senescence. This review synthesises evidence from molecular endocrinology, biochemical, pre-clinical, and clinical models to advance a mechanistically integrated and therapeutically actionable framework that aligns into a unified endocrine, metabolic, and immune target-driven framework relevant to complex, inflammation-driven brain ageing, thereby offering a strong foundation and paving the way for future molecular target validation and disease-modifying, steroid-mimetic interventions against neurodegeneration.