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Brain vascular aging is increasingly recognized as a critical therapeutic target for age-related cognitive decline. Oxidative stress, bioenergetic dysfunction, and molecular damage play central roles in the progression of vascular aging, contributing to cerebrovascular dysfunction and impaired cognitive function. While naturally occurring polyphenols such as resveratrol (RSV) have demonstrated potential in mitigating aging-related pathologies, their poor bioavailability and limited brain targeting efficiency significantly constrain their therapeutic impact. As a result, high doses or advanced drug delivery strategies are necessary to achieve meaningful physiological effects. We introduce a novel nanocarrier system designed to enhance RSV delivery to the cerebral endothelium by leveraging the natural formation of an apolipoprotein E (ApoE)-enriched protein corona around fusogenic liposomes (FL) Show less

Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood. Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E ( We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E ( Show less

Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE Show less

Genetic polymorphisms in cardiovascular disease (CVD) susceptibility across different ethnic groups is highly imperetive. Therefore, it is of interest to investigate the role of genetic polymorphisms in cardiovascular disease (CVD) susceptibility across different ethnic groups. Participants were tested for variations in LDLR, APOE and LPL genes and their association with cardiovascular risk factors such as cholesterol levels and blood pressure was examined. Data shows ethnic differences in the prevalence of these polymorphisms, suggesting that genetic factors contribute to CVD risk in a population-specific manner. Thus, we show the need for personalized cardiovascular risk assessment strategies. The ethnic-specific distribution of genetic polymorphisms (LDLR, APOE and LPL) linked to cardiovascular disease susceptibility, highlighting the need for personalized cardiovascular risk assessment strategies based on genetic and ethnic factors is highlighted. Show less

Atherosclerosis is the leading cause of heart attack and stroke worldwide. The key characteristic of atherosclerosis is accumulation of LDL cholesterol in artery walls, the subsequent infiltration by monocytes/macrophages, and the development of inflammation. Recently, we reported that plasma protein complement factor H-related 1 (FHR1) binds to the necrotic surfaces of cardiovascular plaques and induces inflammation. Moreover, the concentration of FHR1 is higher, whereas Show less

Aortic valve disease (AVD) is a cardiovascular disorder highly prevalent in the elderly population. Aortic valve leaflets suffer hardening due to extracellular matrix (ECM) remodeling and subsequent calcification, leading to impaired blood flow and aortic valve stenosis. Valve interstitial cells (VICs) are fibroblast-like cells that can undergo myofibroblast activation and osteogenic transformation, contributing to disease progression. We performed a bioinformatic re-analysis of a publicly available scRNA-seq dataset to identify pathogenic VIC subpopulations and characterize cell-cell communication networks relevant to early AVD. Re-analysis of scRNA-seq data from aortic valves of These findings suggests the presence of a disease-associated VIC Spp1 Show less

Atherosclerosis (AS) is a central pathological driver underlying most cardiovascular diseases. Gut microbiota and related metabolites participate in regulating atherosclerosis. Fifty C57BL/6J ApoE Atherosclerotic plaques accumulated in the aorta and aortic sinus after HFD, while statin and high-dose GP alleviated this burden. TC, TG, LDL-C, MCP-1, MCP-3 and IL-2 showed significant increase after HFD, while statin and GP decreased LDL-C, MCP-1 and MCP-3. The goblet cells, ZO-1 and Occludin decreased after HFD, while statin and GP increased them, indicating that the intestinal barrier integrity was improved. Additionally, the composition of gut microbiota was modulated by GP. Some candidate taxa were identified, such as This study suggests that GP is beneficial for alleviating atherosclerosis in HFD-induced ApoE Show less

Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) has been implicated in cell death, glucose homeostasis, and tumor progression, yet its role in atherosclerosis (AS) remains unclear. In this study, SNHG5 expression was markedly elevated in aortic tissues of high-fat diet-fed apoE Show less

Atherosclerosis (AS) is linked to many cardiovascular disorders. We investigated the potential roles and mechanisms of microRNA (miR)-218-5p in AS. Primary mouse aortic endothelial cells (MAECs) were induced with ox-LDL, followed by various interventions including miR/gene overexpression and knockdown. An AS mouse model was established in ApoE Show less

This study determines the phenotypic and functional characteristics that define distinct fibroblast-like synoviocyte (FLS) populations in rheumatoid arthritis (RA) vs psoriatic arthritis (PsA). Single-cell RNA sequencing and multiparametric flow cytometry analysis (21 markers) were performed on RA and PsA synovial cell suspensions to determine FLS phenotype/function. Podoplanin (PDPN) Flow analysis of PDPN RA and PsA possess distinct FLS populations with unique functional and metabolic properties, which may facilitate improved understanding of disease pathogenesis and therapeutic response. Show less

Healthy aging is a complex process influenced by genetic, environmental, and lifestyle factors. Although prior genetic studies have identified loci associated with longevity, replication has often been limited by strong non-genetic influences. To investigate the genetic contributors to healthy aging, we performed a genome-wide association study (GWAS) and pathway analyses in 597 Super Seniors-individuals aged ≥ 85 years with no history of cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease-compared to 420 mid-life population-based controls that represent the population before selection for survival from age-related disorders. Candidate variant analyses confirmed known associations at the APOE locus, where APOE4 carriers had reduced odds of healthy aging (P = 0.0025), with stronger effects in females (P = 8.82 × 10⁻ Show less

Blood-based biomarkers are increasingly used to characterize Alzheimer's disease (AD)-related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau Show less

BackgroundThe Montreal Cognitive Assessment (MoCA) is widely used for cognitive screening. Despite numerous studies showing that MoCA scores are affected by demographic variables including age, education, and race, the instrument is typically evaluated using a raw score or simple one-point education correction in clinical practice.ObjectiveIn this study, we comprehensively evaluate the diagnostic accuracy of the MoCA in a large cohort of individuals being evaluated for mild cognitive impairment or dementia.MethodsWe used data from the National Alzheimer's Coordinating Center (NACC) database to examine diagnostic accuracy of the MoCA, using both raw scores and Z-scores subject to non-linear demographic correction. We present comprehensive accuracy statistics, concordance with Show less

Apolipoprotein E (APOE) plays a tissue-specific role in diet-induced obesity: brain-expressed APOE promotes obesity, while hepatic APOE appears protective. Physiological plasma APOE levels facilitate clearance of atherogenic lipoproteins; however, supraphysiological levels induce hypertriglyceridemia and impair cholesterol clearance. APOE-induced hypertriglyceridemia has been linked to its carboxyl-terminal region (amino acids 260-270), particularly residues L261, W264, F265, L268, and V269. A bioengineered APOE4 variant, APOE4mut1, where these residues are substituted with alanine, promotes cholesterol clearance without inducing hypertriglyceridemia at any level of expression. This study examined APOE4mut1 effects on adipose tissue metabolism in vivo. Wild-type (C57BL/6) and APOE4 Show less

Conventional nanocarriers are readily cleared by macrophages in the liver, with only a minimal fraction reaching hepatocytes. This limitation has been effectively overcome in clinically approved lipid nanoparticles (LNPs) through the incorporation of ionizable lipids. Inspired by this property, we explored whether incorporating ionizable lipids into the lipid bilayer membrane of mesoporous silica nanoparticles (silicasomes) could similarly enhance their hepatic cellular uptake. We developed ionizable silicasomes (I-silicasomes) and systematically compared them with ionizable liposomes (I-liposomes), as well as their conventional counterparts (C-silicasomes and C-liposomes). Surprisingly, I-silicasomes did not enhance hepatocyte uptake Show less

G9A, a histone methyltransferase that facilitates H3K9 dimethylation, has been implicated in the epigenetic regulation of vascular processes. This study encapsulates its involvement in the calcification and stability of atherosclerotic plaques, further investigating its interaction with bone morphogenetic protein 2 (BMP2), a pivotal factor in vascular calcification, unveiling that G9A fosters plaque calcification and instability via the BMP2 signaling pathway. The progression of unstable plaques, histone methylation status, and vascular calcification incidence were monitored in the carotid plaques of ApoE In ApoE Our findings indicate that G9A amplifies vascular calcification through the activation of Bmp2 signaling, a fundamental mediator of vascular calcification. The relationship between vascular calcification and the emergence of unstable plaques may be intricately associated with histone methylation. Show less

Alzheimer's disease pathology (ADP) and Lewy body pathology (LBP) are traditionally associated with distinct cognitive profiles. However, growing evidence highlights the role of behavioral and psychological symptoms of dementia (BPSD) in shaping clinical presentations. The combined influence of cognitive and behavioral symptoms across neuropathologically confirmed ADP, LBP, and mixed AD-LBP has not been systematically examined. This study aimed to identify clinically meaningful subtypes by jointly analyzing cognitive performance and BPSD profiles in individuals with autopsy-confirmed dementia pathology. This retrospective longitudinal cohort study used data from the National Alzheimer Coordinating Center (NACC), collected across multiple U.S. Alzheimer's Disease Research Centers. Participants had a Clinical Dementia Rating (CDR) Global score ≤1 at baseline and autopsy-confirmed ADP, LBP, or mixed AD-LBP. Cognitive outcomes included standardized tests of memory, executive function, and language. BPSD were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), which captures ten symptom domains: agitation, apathy, depression, delusions, disinhibition, auditory and visual hallucinations, irritability, personality change, and REM sleep behavior disorder. Cluster analysis was applied to identify subtypes based on combined cognitive and BPSD data. The study included 1,028 participants (mean age at baseline 76.4 years; 47.6% female): 521 with ADP, 96 with LBP, and 411 with mixed AD-LBP. A three-cluster clinical subtype (CS) solution best fit the data. The most symptomatic group (CS-3) had the youngest age at first visit (mean 72.1 years), the highest BPSD burden, and the fastest cognitive and functional decline across ADP and AD-LBP groups. CS-1 and CS-2 exhibited milder early cognitive impairment and lower BPSD burden. Within ADP and AD-LBP, CS-2 showed slower progression than CS-1, fewer APOE ε4 carriers (41% vs. 58%), and better memory scores, despite reporting a higher frequency of agitation. These findings reveal distinct clinical subtypes that cut across traditional pathological boundaries, emphasizing the need to incorporate both cognitive and behavioral features into early dementia characterization. This multidimensional approach can improve guide personalized prognosis and care planning and enhance clinical trial design by considering disease heterogeneity. The study supports integrated clinical profiling as important factor in robust evaluation of dementia outcomes. Show less

Lecanemab binds "protofibrils," which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid-related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms. Equilibrium binding constants (K Lecanemab and aducanumab had indistinguishable preference for "protofibrils." Antibody preference for plaque-enriched versus CAA-enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody-accessible Aβ. Lecanemab's binding target is similar to other antibodies'. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates. Show less

BackgroundAlzheimer's disease (AD) has been reported to be associated with changes in inflammatory levels, although further research is needed. This study focused on identifying specific inflammatory biomarkers in peripheral blood that could differentiate patients with AD from healthy control subjects.ObjectiveThe primary objective was to determine whether a selection of peripheral blood inflammatory biomarkers could serve as a diagnostic tool for AD.MethodsA multicenter study was conducted, comparing 39 patients with AD to 27 healthy controls. AD diagnosis was confirmed through a comprehensive evaluation, including the Mini-Mental State Examination and analysis of cerebrospinal fluid or positron emission tomography. Thirteen inflammatory markers were measured, and logistic regression analysis was used to assess their discriminatory potential. The relationship between the Show less

Air pollution is linked to dementia, but evidence from low-exposure settings is limited. We examined sex-specific associations between long-term exposure to fine particulate matter ≤2.5 µm in diameter (PM2.5) and dementia risk in older adults living in Australia. In 16,145 dementia-free Aspirin in Reducing Events in the Elderly (ASPREE) participants (≥70 years; median follow-up 10.3 years), Cox models assessed associations between 1-year mean PM2.5 (continuous and guideline-based categories) and incident dementia, adjusting for demographic, lifestyle, environmental, and genetic factors. Subgroup analyses by sex, apolipoprotein E genotype (APOE), and age were conducted. Overall associations were null, but with a trend for increased risk at exposures >10 versus ≤5 µg/m Findings suggest a threshold of >10 µg/m Show less

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Unfortunately, the early stages of this disease are poorly understood, which has led to limited treatment options. Investigating normal changes in tissues eventually affected by AMD can further elucidate the mechanisms of disease progression and lead to novel therapeutic targets. The primary cell layer affected in AMD is the retinal pigment epithelium (RPE), which forms the outer blood-retinal barrier (oBRB). Beneath the RPE lies Bruch's membrane, a proteinaceous layer that naturally thickens and stiffens with age. These changes to Bruch's membrane are also implicated in RPE dysfunction and AMD progression. To investigate the relationship between normal, age-related changes in Bruch's membrane and AMD development, we engineered a tunable in vitro model of Bruch's membrane to support primary porcine RPE cells. We performed transepithelial electrical resistance (TEER) measurements, viability assays, morphological analysis, immunocytochemistry, and enzyme-linked immunosorbent assays (ELISA) to evaluate monolayer integrity and angiogenic factor expression. Cells cultured on our aged model exhibited changes similar to those seen in AMD, including reduced monolayer integrity, the formation of sub-RPE deposits, and eventual cell death. Notably, apolipoprotein E (ApoE), a known drusen component and Alzheimer's disease marker, was overexpressed prior to deposit accumulation and cell death. Regions of ApoE overexpression corresponded with disrupted expression of zonula occludens-1, a junctional protein. While most angiogenic factors remained unchanged, tissue inhibitor of metalloproteinases-1 (TIMP-1) was transiently overexpressed before cell death. These findings suggest that ApoE and TIMP-1 may play key roles in early AMD pathogenesis and represent potential targets for future therapeutic intervention. Show less

Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all-cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD/dementia, stratifying the analysis based on Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94]; Our study suggests that high blood PCSK9 levels are protective against AD risk in Show less

COG133, an apolipoprotein E-derived mimetic peptide, has been proposed as a therapeutic candidate due to its immunomodulatory properties. Its potential role in diabetic wound healing, where impaired fibroblast function and chronic inflammation are major obstacles, remains largely unexplored. In this study, human diabetic dermal fibroblasts were treated with COG133 to evaluate its effects on cell viability, migration, and gene expression of ApoE, miR-146a, NF-κB, TRAF-6, and IL-6. In addition, the antibacterial and antibiofilm activities of COG133 were assessed against Gram-positive and Gram-negative bacteria. COG133 enhanced fibroblast migration without affecting viability, upregulated miR-146a, and reduced IL-6 and ApoE expression, while NF-κB and TRAF-6 remained unchanged. Antibacterial assays revealed inhibitory effects, with the lowest MIC against Show less

Abdominal aortic aneurysms (AAAs) are characterized by ECM (extracellular matrix) degradation and chronic vascular inflammation, with macrophages playing a key role. The mechanisms regulating macrophage activation in AAA remain incompletely understood. Vascular macrophages express Olfr2 (olfactory receptor 2), a GPCR (G-protein-coupled receptor) implicated in inflammation, but its role in AAA development is unknown. We investigated the role of Olfr2 in AAA using PPE (porcine pancreatic elastase) infusion in Olfr2-deficient ( Microarray analysis revealed increased expression of the human Olfr2 regulates monocyte recruitment and macrophage-driven inflammation during AAA. Its genetic deletion or pharmacological inhibition protects against AAA, whereas receptor activation worsens the disease. Olfr2 represents a critical modulator of vascular inflammation and a potential therapeutic target in AAA. Show less