Pub Date : 2024-09-05eCollection Date: 2024-01-01DOI: 10.3233/ADR-240026
Yiwen Yang, Ming Tong, Suzanne M de la Monte
Background: Alzheimer's disease (AD), one of the most prevalent causes of dementia, is mainly sporadic in occurrence but driven by aging and other cofactors. Studies suggest that excessive alcohol consumption may increase AD risk.
Objective: Our study examined the degree to which short-term moderate ethanol exposure leads to molecular pathological changes of AD-type neurodegeneration.
Methods: Long Evans male and female rats were fed for 2 weeks with isocaloric liquid diets containing 24% or 0% caloric ethanol (n = 8/group). The frontal lobes were used to measure immunoreactivity to AD biomarkers, insulin-related endocrine metabolic molecules, and proinflammatory cytokines/chemokines by duplex or multiplex enzyme-linked immunosorbent assays (ELISAs).
Results: Ethanol significantly increased frontal lobe levels of phospho-tau, but reduced Aβ, ghrelin, glucagon, leptin, PAI, IL-2, and IFN-γ.
Conclusions: Short-term effects of chronic ethanol feeding produced neuroendocrine molecular pathologic changes reflective of metabolic dysregulation, together with abnormalities that likely contribute to impairments in neuroplasticity. The findings suggest that chronic alcohol consumption rapidly establishes a platform for impairments in energy metabolism that occur in both the early stages of AD and alcohol-related brain degeneration.
背景:阿尔茨海默病(AD)是最常见的痴呆症病因之一,主要为偶发性,但受衰老和其他辅助因素的影响。研究表明,过量饮酒可能会增加痴呆症的风险:我们的研究探讨了短期中度乙醇暴露导致 AD 型神经退行性变的分子病理变化的程度:方法:用含24%或0%热量乙醇的等热量液态食物喂养长埃文斯雌雄大鼠2周(n = 8只/组)。用双联或多重酶联免疫吸附试验(ELISA)测量大鼠额叶对AD生物标志物、胰岛素相关内分泌代谢分子和促炎细胞因子/凝血因子的免疫反应性:结果:乙醇明显增加了额叶磷酸化-陶的水平,但降低了Aβ、胃泌素、胰高血糖素、瘦素、PAI、IL-2和IFN-γ的水平:结论:慢性乙醇喂养的短期效应产生了反映代谢失调的神经内分泌分子病理变化,以及可能导致神经可塑性损伤的异常。研究结果表明,长期饮酒会迅速为能量代谢障碍建立一个平台,而能量代谢障碍会在注意力缺失症和酒精相关脑退化的早期阶段出现。
{"title":"Early-Stage Moderate Alcohol Feeding Dysregulates Insulin-Related Metabolic Hormone Expression in the Brain: Potential Links to Neurodegeneration Including Alzheimer's Disease.","authors":"Yiwen Yang, Ming Tong, Suzanne M de la Monte","doi":"10.3233/ADR-240026","DOIUrl":"10.3233/ADR-240026","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD), one of the most prevalent causes of dementia, is mainly sporadic in occurrence but driven by aging and other cofactors. Studies suggest that excessive alcohol consumption may increase AD risk.</p><p><strong>Objective: </strong>Our study examined the degree to which short-term moderate ethanol exposure leads to molecular pathological changes of AD-type neurodegeneration.</p><p><strong>Methods: </strong>Long Evans male and female rats were fed for 2 weeks with isocaloric liquid diets containing 24% or 0% caloric ethanol (<i>n</i> = 8/group). The frontal lobes were used to measure immunoreactivity to AD biomarkers, insulin-related endocrine metabolic molecules, and proinflammatory cytokines/chemokines by duplex or multiplex enzyme-linked immunosorbent assays (ELISAs).</p><p><strong>Results: </strong>Ethanol significantly increased frontal lobe levels of phospho-tau, but reduced Aβ, ghrelin, glucagon, leptin, PAI, IL-2, and IFN-<i>γ</i>.</p><p><strong>Conclusions: </strong>Short-term effects of chronic ethanol feeding produced neuroendocrine molecular pathologic changes reflective of metabolic dysregulation, together with abnormalities that likely contribute to impairments in neuroplasticity. The findings suggest that chronic alcohol consumption rapidly establishes a platform for impairments in energy metabolism that occur in both the early stages of AD and alcohol-related brain degeneration.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05eCollection Date: 2024-01-01DOI: 10.3233/ADR-240062
Ying Wang, Xinhua Song, Rui Wang, Xinzi Xu, Yaming Du, Guohua Chen, Junhua Mei
Background: Alzheimer's disease (AD) currently lacks effective disease-modifying treatments. Recent research suggests that ferroptosis could be a potential therapeutic target. Mendelian randomization (MR) is a widely used method for identifying novel therapeutic targets.
Objective: Employ genetic information to evaluate the causal impact of ferroptosis-related genes on the risk of AD.
Methods: 564 ferroptosis-related genes were obtained from FerrDb. We derived genetic instrumental variables for these genes using four brain quantitative trait loci (QTL) and two blood QTL datasets. Summary-data-based Mendelian randomization (SMR) and two-sample MR methods were applied to estimate the causal effects of ferroptosis-related genes on AD. Using extern transcriptomic datasets and triple-transgenic mouse model of AD (3xTg-AD) to further validate the gene targets identified by the MR analysis.
Results: We identified 17 potential AD risk gene targets from GTEx, 13 from PsychENCODE, and 22 from BrainMeta (SMR p < 0.05 and HEIDI test p > 0.05). Six overlapping ferroptosis-related genes associated with AD were identified, which could serve as potential therapeutic targets (PEX10, CDC25A, EGFR, DLD, LIG3, and TRIB3). Additionally, we further pinpointed risk genes or proteins at the blood tissue and pQTL levels. Notably, EGFR demonstrated significant dysregulation in the extern transcriptomic datasets and 3xTg-AD models.
Conclusions: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the six druggable genes for AD treatment, especially for EGFR (validated by transcriptome and 3xTg-AD), which could be useful for prioritizing AD drug development in the field of ferroptosis.
背景:阿尔茨海默病(AD)目前缺乏有效的疾病改变疗法。最近的研究表明,铁突变可能是一个潜在的治疗靶点。孟德尔随机化(MR)是一种广泛应用于确定新型治疗靶点的方法:方法:我们从 FerrDb 中获得了 564 个与铁氧化相关的基因。我们利用四个脑定量性状位点(QTL)和两个血液QTL数据集得出了这些基因的遗传工具变量。我们采用基于摘要数据的孟德尔随机化(SMR)和双样本 MR 方法来估计铁突变相关基因对 AD 的因果效应。利用外部转录组数据集和三重转基因小鼠AD模型(3xTg-AD)进一步验证MR分析确定的基因靶标:结果:我们从GTEx、PsychENCODE和BrainMeta中分别发现了17个、13个和22个潜在的AD风险基因靶点(SMR p p > 0.05)。我们发现了 6 个与 AD 相关的重叠铁蛋白沉积相关基因,这些基因可作为潜在的治疗靶点(PEX10、CDC25A、表皮生长因子受体、DLD、LIG3 和 TRIB3)。此外,我们还进一步确定了血液组织和 pQTL 水平上的风险基因或蛋白。值得注意的是,表皮生长因子受体在外部转录组数据集和 3xTg-AD 模型中表现出明显的失调:本研究提供的遗传学证据支持了靶向治疗AD的六个可药用基因的潜在治疗效果,尤其是表皮生长因子受体(通过转录组和3xTg-AD验证),这可能有助于在铁变态反应领域优先开发AD药物。
{"title":"Genome-Wide Mendelian Randomization Identifies Ferroptosis-Related Drug Targets for Alzheimer's Disease.","authors":"Ying Wang, Xinhua Song, Rui Wang, Xinzi Xu, Yaming Du, Guohua Chen, Junhua Mei","doi":"10.3233/ADR-240062","DOIUrl":"10.3233/ADR-240062","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) currently lacks effective disease-modifying treatments. Recent research suggests that ferroptosis could be a potential therapeutic target. Mendelian randomization (MR) is a widely used method for identifying novel therapeutic targets.</p><p><strong>Objective: </strong>Employ genetic information to evaluate the causal impact of ferroptosis-related genes on the risk of AD.</p><p><strong>Methods: </strong>564 ferroptosis-related genes were obtained from FerrDb. We derived genetic instrumental variables for these genes using four brain quantitative trait loci (QTL) and two blood QTL datasets. Summary-data-based Mendelian randomization (SMR) and two-sample MR methods were applied to estimate the causal effects of ferroptosis-related genes on AD. Using extern transcriptomic datasets and triple-transgenic mouse model of AD (3xTg-AD) to further validate the gene targets identified by the MR analysis.</p><p><strong>Results: </strong>We identified 17 potential AD risk gene targets from GTEx, 13 from PsychENCODE, and 22 from BrainMeta (SMR <i>p</i> < 0.05 and HEIDI test <i>p</i> > 0.05). Six overlapping ferroptosis-related genes associated with AD were identified, which could serve as potential therapeutic targets <i>(PEX10, CDC25A, EGFR, DLD, LIG3,</i> and <i>TRIB3</i>). Additionally, we further pinpointed risk genes or proteins at the blood tissue and pQTL levels. Notably, <i>EGFR</i> demonstrated significant dysregulation in the extern transcriptomic datasets and 3xTg-AD models.</p><p><strong>Conclusions: </strong>This study provides genetic evidence supporting the potential therapeutic benefits of targeting the six druggable genes for AD treatment, especially for <i>EGFR</i> (validated by transcriptome and 3xTg-AD), which could be useful for prioritizing AD drug development in the field of ferroptosis.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05eCollection Date: 2024-01-01DOI: 10.3233/ADR-240104
Min Xiong, Hongji You, Wang Liao, Yingren Mai, Xiaoming Luo, Yipei Liu, Sheng-Nan Jiang
Background: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is valuable in Alzheimer's disease (AD) workup.
Objective: To explore the effectiveness of 18F-FDG PET in differentiating and staging AD and associations between brain glucose metabolism and cognitive functions and vascular risk factors.
Methods: 107 participates including 19 mild cognitive impairment (MCI), 38 mild AD, 24 moderate AD, 15 moderate-severe AD, and 11 frontotemporal dementia (FTD) were enrolled. Visual and voxel-based analysis procedures were utilized. Cognitive conditions, including 6 cognitive function scores and 7 single-domain cognitive performances, and vascular risk factors linked to hypertension, hyperlipidemia, diabetes, and obesity were correlated with glucose metabolism in AD dementia using age as a covariate.
Results: 18F-FDG PET effectively differentiated AD from FTD and also differentiated MCI from AD subtypes with significantly different hypometabolism (except for mild AD) (height threshold p < 0.001, all puncorr < 0.05, the same below). The cognitive function scores, notably Mini-Mental State Examination and Montreal Cognitive Assessment, correlated significantly with regional glucose metabolism in AD participants (all p < 0.05), whereas the single-domain cognitive performance and vascular risk factors were significantly associated with regional glucose metabolism in MCI patients (all p < 0.05).
Conclusions: This study underlines the vital role of 18F-FDG PET in identifying and staging AD. Brain glucose metabolism is associated with cognitive status in AD dementia and vascular risk factors in MCI, indicating that 18F-FDG PET might be promising for predicting cognitive decline and serve as a visual framework for investigating underlying mechanism of vascular risk factors influencing the conversion from MCI to AD.
背景:18F-氟脱氧葡萄糖(18F-FDG)正电子发射断层扫描(PET)在阿尔茨海默病(AD)检查中具有重要价值:目的:探讨18F-FDG正电子发射断层扫描在区分和分期AD方面的有效性,以及脑葡萄糖代谢与认知功能和血管风险因素之间的关联。方法:纳入107名参与者,包括19名轻度认知障碍患者(MCI)、38名轻度AD患者、24名中度AD患者、15名中度重度AD患者和11名额颞叶痴呆患者(FTD)。采用了视觉分析和基于体素的分析程序。将年龄作为协变量,将认知条件(包括 6 项认知功能评分和 7 项单域认知表现)以及与高血压、高脂血症、糖尿病和肥胖有关的血管风险因素与 AD 痴呆症患者的葡萄糖代谢相关联:结果:18F-FDG PET 能有效区分 AD 和 FTD,还能区分 MCI 和 AD 亚型,它们的糖代谢显著不同(轻度 AD 除外)(身高阈值 p puncorr p p 结论:18F-FDG PET 能有效区分 AD 和 FTD,还能区分 MCI 和 AD 亚型,它们的糖代谢显著不同(轻度 AD 除外):本研究强调了 18F-FDG PET 在识别和分期 AD 方面的重要作用。脑糖代谢与AD痴呆症的认知状态和MCI的血管风险因素相关,这表明18F-FDG PET有望预测认知功能衰退,并可作为研究影响MCI向AD转化的血管风险因素潜在机制的直观框架。
{"title":"The Association Between Brain Metabolic Biomarkers Using <sup>18</sup>F-FDG and Cognition and Vascular Risk Factors, as well as Its Usefulness in the Diagnosis and Staging of Alzheimer's Disease.","authors":"Min Xiong, Hongji You, Wang Liao, Yingren Mai, Xiaoming Luo, Yipei Liu, Sheng-Nan Jiang","doi":"10.3233/ADR-240104","DOIUrl":"10.3233/ADR-240104","url":null,"abstract":"<p><strong>Background: </strong><sup>18</sup>F-fluorodeoxyglucose (<sup>18</sup>F-FDG) positron emission tomography (PET) is valuable in Alzheimer's disease (AD) workup.</p><p><strong>Objective: </strong>To explore the effectiveness of <sup>18</sup>F-FDG PET in differentiating and staging AD and associations between brain glucose metabolism and cognitive functions and vascular risk factors.</p><p><strong>Methods: </strong>107 participates including 19 mild cognitive impairment (MCI), 38 mild AD, 24 moderate AD, 15 moderate-severe AD, and 11 frontotemporal dementia (FTD) were enrolled. Visual and voxel-based analysis procedures were utilized. Cognitive conditions, including 6 cognitive function scores and 7 single-domain cognitive performances, and vascular risk factors linked to hypertension, hyperlipidemia, diabetes, and obesity were correlated with glucose metabolism in AD dementia using age as a covariate.</p><p><strong>Results: </strong><sup>18</sup>F-FDG PET effectively differentiated AD from FTD and also differentiated MCI from AD subtypes with significantly different hypometabolism (except for mild AD) (height threshold <i>p</i> < 0.001, all <i>puncorr</i> < 0.05, the same below). The cognitive function scores, notably Mini-Mental State Examination and Montreal Cognitive Assessment, correlated significantly with regional glucose metabolism in AD participants (all <i>p</i> < 0.05), whereas the single-domain cognitive performance and vascular risk factors were significantly associated with regional glucose metabolism in MCI patients (all <i>p</i> < 0.05).</p><p><strong>Conclusions: </strong>This study underlines the vital role of <sup>18</sup>F-FDG PET in identifying and staging AD. Brain glucose metabolism is associated with cognitive status in AD dementia and vascular risk factors in MCI, indicating that <sup>18</sup>F-FDG PET might be promising for predicting cognitive decline and serve as a visual framework for investigating underlying mechanism of vascular risk factors influencing the conversion from MCI to AD.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05eCollection Date: 2024-01-01DOI: 10.3233/ADR-240067
Serena Low, Angela Moh, Kiat Sern Goh, Jonathon Khoo, Keven Ang, Allen Yan Lun Liu, Wern Ee Tang, Ziliang Lim, Tavintharan Subramaniam, Chee Fang Sum, Su Chi Lim
Background: Decline in renal function impairs systemic clearance of amyloid-β which characterizes Alzheimer's disease while albuminuria is associated with blood-brain barrier disruption due to endothelial damage. Arterial stiffness adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels.
Objective: To examine association between a novel kidney disease index (KDI), which is a composite index of estimated glomerular filtration (eGFR) and urinary albumin-to-creatinine ratio (uACR), and cognitive function with potential mediation by arterial stiffness.
Methods: This was a longitudinal multi-center study of participants with type 2 diabetes (T2D) aged 45 years and above. We assessed cognitive function with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pulse wave velocity (PWV), an index of arterial stiffness, was measured using applanation tonometry method. KDI was calculated as geometric mean of 1/eGFR and natural logarithmically-transformed (ln)(ACR*100).
Results: There were 1,303 participants with mean age 61.3±8.0 years. LnKDI was associated with lower baseline RBANS total score with adjusted coefficient -2.83 (95% CI -4.30 to -1.35; p < 0.001). 590 participants were followed over up to 8.6 years. LnKDI was associated with lower follow-up RBANS score in total, immediate memory, visuo-spatial/construction and attention domains with corresponding adjusted coefficients -2.35 (95% CI -4.50 to -0.20; p = 0.032), -2.93 (95% CI -5.84 to -0.02; p = 0.049), -3.26 (95% CI -6.25 to -0.27; p = 0.033) and -4.88 (95% CI -7.95 to -1.82; p = 0.002). PWV accounted for 19.5% of association between and follow-up RBANS total score.
Conclusions: KDI was associated with lower cognitive function globally, and in immediate memory, visuo-spatial/construction and attention domains. Arterial stiffness mediated the association between KDI and cognitive decline in patients with T2D.
背景:肾功能衰退会影响淀粉样蛋白-β的全身清除,而白蛋白尿则与内皮损伤导致的血脑屏障破坏有关。动脉僵化会对大脑产生不利影响,高脉动流量会损害脑微血管:目的:研究一种新型肾脏疾病指数(KDI)(估计肾小球滤过率(eGFR)和尿白蛋白-肌酐比值(uACR)的综合指数)与认知功能之间的关系,以及动脉僵化可能起到的中介作用:这是一项针对 45 岁及以上 2 型糖尿病(T2D)患者的多中心纵向研究。我们使用神经心理状态评估可重复性电池(RBANS)评估认知功能。脉搏波速度(PWV)是动脉僵化的一个指标,采用眼压测量法进行测量。KDI以1/eGFR和自然对数转换(ln)(ACR*100)的几何平均数计算:结果:共有 1303 名参与者,平均年龄(61.3±8.0)岁。LnKDI与较低的基线RBANS总分相关,调整系数分别为-2.83 (95% CI -4.30 to -1.35; p p = 0.032)、-2.93 (95% CI -5.84 to -0.02; p = 0.049)、-3.26 (95% CI -6.25 to -0.27; p = 0.033)和-4.88 (95% CI -7.95 to -1.82; p = 0.002)。脉搏波速度占RBANS总分与随访之间关系的19.5%:结论:KDI与整体认知功能较低、即时记忆、视觉空间/建构和注意力领域的认知功能较低有关。动脉僵化介导了 KDI 与 T2D 患者认知功能下降之间的关系。
{"title":"Association Between Kidney Disease Index and Decline in Cognitive Function with Mediation by Arterial Stiffness in Asians with Type 2 Diabetes.","authors":"Serena Low, Angela Moh, Kiat Sern Goh, Jonathon Khoo, Keven Ang, Allen Yan Lun Liu, Wern Ee Tang, Ziliang Lim, Tavintharan Subramaniam, Chee Fang Sum, Su Chi Lim","doi":"10.3233/ADR-240067","DOIUrl":"10.3233/ADR-240067","url":null,"abstract":"<p><strong>Background: </strong>Decline in renal function impairs systemic clearance of amyloid-β which characterizes Alzheimer's disease while albuminuria is associated with blood-brain barrier disruption due to endothelial damage. Arterial stiffness adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels.</p><p><strong>Objective: </strong>To examine association between a novel kidney disease index (KDI), which is a composite index of estimated glomerular filtration (eGFR) and urinary albumin-to-creatinine ratio (uACR), and cognitive function with potential mediation by arterial stiffness.</p><p><strong>Methods: </strong>This was a longitudinal multi-center study of participants with type 2 diabetes (T2D) aged 45 years and above. We assessed cognitive function with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pulse wave velocity (PWV), an index of arterial stiffness, was measured using applanation tonometry method. KDI was calculated as geometric mean of 1/eGFR and natural logarithmically-transformed (ln)(ACR*100).</p><p><strong>Results: </strong>There were 1,303 participants with mean age 61.3±8.0 years. LnKDI was associated with lower baseline RBANS total score with adjusted coefficient -2.83 (95% CI -4.30 to -1.35; <i>p</i> < 0.001). 590 participants were followed over up to 8.6 years. LnKDI was associated with lower follow-up RBANS score in total, immediate memory, visuo-spatial/construction and attention domains with corresponding adjusted coefficients -2.35 (95% CI -4.50 to -0.20; <i>p</i> = 0.032), -2.93 (95% CI -5.84 to -0.02; <i>p</i> = 0.049), -3.26 (95% CI -6.25 to -0.27; <i>p</i> = 0.033) and -4.88 (95% CI -7.95 to -1.82; <i>p</i> = 0.002). PWV accounted for 19.5% of association between and follow-up RBANS total score.</p><p><strong>Conclusions: </strong>KDI was associated with lower cognitive function globally, and in immediate memory, visuo-spatial/construction and attention domains. Arterial stiffness mediated the association between KDI and cognitive decline in patients with T2D.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03eCollection Date: 2024-01-01DOI: 10.3233/ADR-240126
Md Ariful Islam, Sudhir Kshirsagar, Arubala P Reddy, Ujala Sehar, P Hemachandra Reddy
Several decades of research on cell and animal models contributed tremendously to understanding human diseases. Particularly, research on rodents and non-human primates revealed that animal research is a major and important component in biomedical research in learning complex pathophysiological processes. Further, animal research helped us to understand human diseases, such as Alzheimer's disease. In addition, animal research has also helped us to test hundreds of drugs and develop treatments for human use. Researchers can gain a better understanding of key biological and physiological processes in humans by comparing them to laboratory animals. Based on their relevance and resemblance to people, or even usual living conditions, scientists rationalize the use of particular animal models in their studies. It is suggested that in the National Institutes of Health and other agencies-funded research, animal models should be carefully selected to study the biology and pathophysiology of human health and diseases such as Alzheimer's disease and other dementias. However, it is critical to use a minimum number of animals for human research. Further, it is also noted that the use and reuse of behavioral, molecular, and biochemical data from wild-type (WT) control mice with mutant lines of disease models, as long as the genetic background is the same in both WT and disease mice. On the other hand, anonymous readers have challenged the use and reuse of WT mice data for comparison. In the current article, we discuss the minimum utility of animals, covering the 3Rs, Replacement, Reduction, and Refinement, and also discuss the use and reuse of behavioral, molecular, and biochemical data.
{"title":"Use and Reuse of Animal Behavioral, Molecular, and Biochemical Data in Alzheimer's Disease Research: Focus on 3Rs and Saving People's Tax Dollars.","authors":"Md Ariful Islam, Sudhir Kshirsagar, Arubala P Reddy, Ujala Sehar, P Hemachandra Reddy","doi":"10.3233/ADR-240126","DOIUrl":"10.3233/ADR-240126","url":null,"abstract":"<p><p>Several decades of research on cell and animal models contributed tremendously to understanding human diseases. Particularly, research on rodents and non-human primates revealed that animal research is a major and important component in biomedical research in learning complex pathophysiological processes. Further, animal research helped us to understand human diseases, such as Alzheimer's disease. In addition, animal research has also helped us to test hundreds of drugs and develop treatments for human use. Researchers can gain a better understanding of key biological and physiological processes in humans by comparing them to laboratory animals. Based on their relevance and resemblance to people, or even usual living conditions, scientists rationalize the use of particular animal models in their studies. It is suggested that in the National Institutes of Health and other agencies-funded research, animal models should be carefully selected to study the biology and pathophysiology of human health and diseases such as Alzheimer's disease and other dementias. However, it is critical to use a minimum number of animals for human research. Further, it is also noted that the use and reuse of behavioral, molecular, and biochemical data from wild-type (WT) control mice with mutant lines of disease models, as long as the genetic background is the same in both WT and disease mice. On the other hand, anonymous readers have challenged the use and reuse of WT mice data for comparison. In the current article, we discuss the minimum utility of animals, covering the 3Rs, Replacement, Reduction, and Refinement, and also discuss the use and reuse of behavioral, molecular, and biochemical data.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Alzheimer's disease (AD) is related to one or more chronic illnesses, which may develop cognitive decline and dementia. Cognitive impairment is increasing, and public health officials must address risk factors for AD to improve the health of rural West Texas communities.
Objective: The purpose of this study was to explore the sociodemographic and chronic disease risk factors related to cognitive impairment among elderly adults living in Cochran, Parmer, and Bailey counties in rural West Texas.
Methods: Statistical methods such as Pearson's chi-squared, proportion tests, univariate binary logistic regression, and a multivariable logistic regression were utilized to analyze data. SPSS software was used to detect the significant relationship between cognitive impairment and risk factors.
Results: Summary statistics were obtained for sociodemographic and chronic diseases by using cross-tabulation analysis and comparing the county respondents with proportion tests. A univariate binary logistic regression method was utilized and found that age group 60-69, anxiety, depression, diabetes, hypertension, and cardiovascular disease were significantly associated with cognitive impairment. Using a multivariable logistic regression approach, it was found that Bailey County (age group 60-69) had a higher likelihood (p = 0.002) of cognitive impairment than Parmer (p = 0.067) and Cochran counties (p = 0.064). The risk of females (p = 0.033) in Parmer County was 78.3% lower compared to males in developing AD.
Conclusions: Identifying significant risk factors for cognitive impairment are important in addressing issues of geographic variations and integrating such factors may guide relevant policy interventions to reduce cognitive impairment incidence in rural communities within West Texas.
{"title":"Comparative Study of Risk Factors Associated with Normal Cognition and Cognitive Impairment in Rural West Elderly Texans.","authors":"Hafiz Khan, Fardous Farhana, Fahad Mostafa, Aamrin Rafiq, Effat Walia Nizia, Refaya Razzaq, Rumana Atique, Megan Dauenhauer, Zawah Zabin, Komaraiah Palle, P Hemachandra Reddy","doi":"10.3233/ADR-240092","DOIUrl":"10.3233/ADR-240092","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is related to one or more chronic illnesses, which may develop cognitive decline and dementia. Cognitive impairment is increasing, and public health officials must address risk factors for AD to improve the health of rural West Texas communities.</p><p><strong>Objective: </strong>The purpose of this study was to explore the sociodemographic and chronic disease risk factors related to cognitive impairment among elderly adults living in Cochran, Parmer, and Bailey counties in rural West Texas.</p><p><strong>Methods: </strong>Statistical methods such as Pearson's chi-squared, proportion tests, univariate binary logistic regression, and a multivariable logistic regression were utilized to analyze data. SPSS software was used to detect the significant relationship between cognitive impairment and risk factors.</p><p><strong>Results: </strong>Summary statistics were obtained for sociodemographic and chronic diseases by using cross-tabulation analysis and comparing the county respondents with proportion tests. A univariate binary logistic regression method was utilized and found that age group 60-69, anxiety, depression, diabetes, hypertension, and cardiovascular disease were significantly associated with cognitive impairment. Using a multivariable logistic regression approach, it was found that Bailey County (age group 60-69) had a higher likelihood (<i>p</i> = 0.002) of cognitive impairment than Parmer (<i>p</i> = 0.067) and Cochran counties (<i>p</i> = 0.064). The risk of females (<i>p</i> = 0.033) in Parmer County was 78.3% lower compared to males in developing AD.</p><p><strong>Conclusions: </strong>Identifying significant risk factors for cognitive impairment are important in addressing issues of geographic variations and integrating such factors may guide relevant policy interventions to reduce cognitive impairment incidence in rural communities within West Texas.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20eCollection Date: 2024-01-01DOI: 10.3233/ADR-230159
Sharareh Ehteshamzad
Background: As the prevalence of Alzheimer's disease (AD) grows with an aging population, the need for early diagnosis has led to increased focus on electroencephalography (EEG) as a non-invasive diagnostic tool.
Objective: This review assesses advancements in EEG analysis, including the application of machine learning, for detecting AD from 2000 to 2023.
Methods: Following PRISMA guidelines, a search across major databases resulted in 25 studies that met the inclusion criteria, focusing on EEG's application in AD diagnosis and the use of novel signal processing and machine learning techniques.
Results: Progress in EEG analysis has shown promise for early AD identification, with techniques like Hjorth parameters and signal compressibility enhancing detection capabilities. Machine learning has improved the precision of differential diagnosis between AD and mild cognitive impairment. However, challenges in standardizing EEG methodologies and data privacy remain.
Conclusions: EEG stands out as a valuable tool for early AD detection, with the potential to integrate into multimodal diagnostic approaches. Future research should aim to standardize EEG procedures and explore collaborative, privacy-preserving research methods.
背景:随着人口老龄化,阿尔茨海默病(AD)的发病率越来越高,对早期诊断的需求促使人们越来越关注脑电图(EEG)这一无创诊断工具:本综述评估了 2000 年至 2023 年间脑电图分析(包括机器学习的应用)在检测 AD 方面取得的进展:按照PRISMA指南,在主要数据库中搜索了25项符合纳入标准的研究,重点关注脑电图在AD诊断中的应用以及新型信号处理和机器学习技术的应用:结果:脑电图分析的进步为早期AD识别带来了希望,Hjorth参数和信号可压缩性等技术提高了检测能力。机器学习提高了 AD 和轻度认知障碍之间鉴别诊断的精确度。然而,脑电图方法标准化和数据隐私方面的挑战依然存在:脑电图是检测早期注意力缺失症的重要工具,具有融入多模态诊断方法的潜力。未来的研究应以脑电图程序标准化为目标,并探索保护隐私的合作研究方法。
{"title":"Assessing the Potential of EEG in Early Detection of Alzheimer's Disease: A Systematic Comprehensive Review (2000-2023).","authors":"Sharareh Ehteshamzad","doi":"10.3233/ADR-230159","DOIUrl":"10.3233/ADR-230159","url":null,"abstract":"<p><strong>Background: </strong>As the prevalence of Alzheimer's disease (AD) grows with an aging population, the need for early diagnosis has led to increased focus on electroencephalography (EEG) as a non-invasive diagnostic tool.</p><p><strong>Objective: </strong>This review assesses advancements in EEG analysis, including the application of machine learning, for detecting AD from 2000 to 2023.</p><p><strong>Methods: </strong>Following PRISMA guidelines, a search across major databases resulted in 25 studies that met the inclusion criteria, focusing on EEG's application in AD diagnosis and the use of novel signal processing and machine learning techniques.</p><p><strong>Results: </strong>Progress in EEG analysis has shown promise for early AD identification, with techniques like Hjorth parameters and signal compressibility enhancing detection capabilities. Machine learning has improved the precision of differential diagnosis between AD and mild cognitive impairment. However, challenges in standardizing EEG methodologies and data privacy remain.</p><p><strong>Conclusions: </strong>EEG stands out as a valuable tool for early AD detection, with the potential to integrate into multimodal diagnostic approaches. Future research should aim to standardize EEG procedures and explore collaborative, privacy-preserving research methods.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-01-01DOI: 10.3233/ADR-240089
Marc L Gordon, Erica Christen, Lynda Keehlisen, Michelle Gong, Fung Lam, Luca Giliberto, Jesus J Gomar, Jeremy Koppel
We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer's disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures.
{"title":"An Open-Label, Pilot Study of Daratumumab SC in Mild to Moderate Alzheimer's Disease.","authors":"Marc L Gordon, Erica Christen, Lynda Keehlisen, Michelle Gong, Fung Lam, Luca Giliberto, Jesus J Gomar, Jeremy Koppel","doi":"10.3233/ADR-240089","DOIUrl":"10.3233/ADR-240089","url":null,"abstract":"<p><p>We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer's disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11305838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-01-01DOI: 10.3233/ADR-230204
Maria Kaltsa, Anthoula Tsolaki, Ioulietta Lazarou, Ilias Mittas, Mairi Papageorgiou, Despina Papadopoulou, Ianthi Maria Tsimpli, Magda Tsolaki
Background: Earlier research focuses primarily on the cognitive changes due to Alzheimer's disease (AD); however, little is known with regard to changes in language competence across the lifespan.
Objective: The present study aims to investigate the decline of language skills at the grammatical and syntactic levels due to changes in cognitive function.
Methods: We administered the Litmus Sentence Repetition Task (SRT) to 150 native speakers of Greek who fall into five groups: 1) young healthy speakers, 2) cognitively intact elder healthy speakers, 3) speakers with subjective cognitive impairment (SCI), 4) speakers with mild cognitive impairment (MCI); and 5) speakers with AD dementia at the mild/moderate stages. All participants underwent a physical and neurological examination and cognitive screening with a standardized neuropsychological battery to assess cognitive status comprehensively and evaluate aspects like working memory, executive function, attention and memory to appropriately classify them.
Results: The data analysis revealed that the SRT had high discriminatory value in the development of AD; specifically, both accuracy and grammaticality indices were related to cognitive decline. Additionally, syntax significantly affected the performance of speakers with structures such as clitics being particularly challenging and in most structures the performance of speakers with MCI drops significantly compared to speakers with SCI.
Conclusions: Linguistic indices revealed subtle early signs of cognitive decline that can be helpful in the early detection of AD, thus facilitating the clinical process offering support to language-based assessment tools such as sentence repetition, a non-invasive type of assessment to evaluate symptoms of AD.
{"title":"Language Markers of Dementia and Their Role in Early Diagnosis of Alzheimer's Disease: Exploring Grammatical and Syntactic Competence via Sentence Repetition.","authors":"Maria Kaltsa, Anthoula Tsolaki, Ioulietta Lazarou, Ilias Mittas, Mairi Papageorgiou, Despina Papadopoulou, Ianthi Maria Tsimpli, Magda Tsolaki","doi":"10.3233/ADR-230204","DOIUrl":"10.3233/ADR-230204","url":null,"abstract":"<p><strong>Background: </strong>Earlier research focuses primarily on the cognitive changes due to Alzheimer's disease (AD); however, little is known with regard to changes in language competence across the lifespan.</p><p><strong>Objective: </strong>The present study aims to investigate the decline of language skills at the grammatical and syntactic levels due to changes in cognitive function.</p><p><strong>Methods: </strong>We administered the Litmus Sentence Repetition Task (SRT) to 150 native speakers of Greek who fall into five groups: 1) young healthy speakers, 2) cognitively intact elder healthy speakers, 3) speakers with subjective cognitive impairment (SCI), 4) speakers with mild cognitive impairment (MCI); and 5) speakers with AD dementia at the mild/moderate stages. All participants underwent a physical and neurological examination and cognitive screening with a standardized neuropsychological battery to assess cognitive status comprehensively and evaluate aspects like working memory, executive function, attention and memory to appropriately classify them.</p><p><strong>Results: </strong>The data analysis revealed that the SRT had high discriminatory value in the development of AD; specifically, both accuracy and grammaticality indices were related to cognitive decline. Additionally, syntax significantly affected the performance of speakers with structures such as clitics being particularly challenging and in most structures the performance of speakers with MCI drops significantly compared to speakers with SCI.</p><p><strong>Conclusions: </strong>Linguistic indices revealed subtle early signs of cognitive decline that can be helpful in the early detection of AD, thus facilitating the clinical process offering support to language-based assessment tools such as sentence repetition, a non-invasive type of assessment to evaluate symptoms of AD.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11305841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Singhrao, Claudia Consoli, Sarah R. Dennison, S. Kanagasingam, R. Welbury
Background: Glycogen synthase-3 kinase (GSK3) is one of the major contributors of tau hyperphosphorylation linked to neurofibrillary tangles in Alzheimer’s disease (AD). Objective: To determine a mechanism of GSK-3β activation by two periodontal bacteria consistently confirmed in AD autopsied brains. Methods: Porphyromonas gingivalis FDC381 and Actinomyces naeslundii ATCC10301 conditioned media were collected. IMR-32 cells were challenged for 48 h with the conditioned media alongside P. gingivalis (ATCC33277) ultrapurified lipopolysaccharide (LPS) designated Pg.LPS under established cell culture conditions either alone or combined. Gene expression and protein analyses for GSK-3β were carried out. Results: qPCR demonstrated that GSK-3β gene was overexpressed in IMR-32 cells treated with Pg.LPS with a 2.09-fold change (p = 0.0005), while A. naeslundii treated cells demonstrated 1.41-fold change (p = 0.004). Western blotting of the cells challenged with Pg.LPS (p = 0.01) and A. naeslundii conditioned medium (p = 0.001) demonstrated the 37 kDa band for each treatment with variable intensity across the medium control. Immunohistochemistry with the GSK-3β of the IMR-32 cells challenged with Pg.LPS and A. naeslundii alone demonstrated cytoplasmic and nuclear localization. Conclusions: Exposure to various bacterial factors upregulated the gene expression of GSK-3β. Western blotting for GSK-3β confirmed the presence of the cleaved fragment by Pg.LPS (37 kDa band p = 0.01) and A. naeslundii conditioned medium (37 kDa band p = 0.001). Immunostaining demonstrated both cytoplasmic and nuclear localization of GSK-3β. Therefore, Pg.LPS and an unknown factor from the A. naeslundii conditioned medium mediated GSK-3β activation via its transcriptionally active, cleaved, fragment. These virulence factors in the body appear to be detrimental to brain health.
背景:糖原合成酶-3 激酶(GSK3)是导致与阿尔茨海默病(AD)神经纤维缠结相关的 tau 过度磷酸化的主要因素之一。研究目的确定两种牙周细菌激活 GSK-3β 的机制,这两种细菌在阿兹海默症(AD)尸检大脑中得到了一致证实。方法:收集牙龈卟啉菌 FDC381 和奈氏放线菌 ATCC10301 条件培养基。在既定的细胞培养条件下,将条件培养基与牙龈卟啉菌(ATCC33277)超纯化脂多糖(LPS)(命名为 Pg.LPS)单独或混合使用,对 IMR-32 细胞进行 48 小时的挑战。对 GSK-3β 进行了基因表达和蛋白质分析。结果:qPCR 显示,经 Pg.LPS 处理的 IMR-32 细胞中 GSK-3β 基因过表达 2.09 倍(p = 0.0005),而经 A. naeslundii 处理的细胞中 GSK-3β 基因过表达 1.41 倍(p = 0.004)。对接受 Pg.LPS (p = 0.01)和 A. naeslundii 条件培养基(p = 0.001)处理的细胞进行 Western 印迹,结果显示每种处理都有 37 kDa 的条带,不同培养基对照的条带强度不同。对单独使用 Pg.LPS 和 A. naeslundii 的 IMR-32 细胞进行的 GSK-3β 免疫组织化学显示了细胞质和细胞核定位。结论暴露于各种细菌因子会上调 GSK-3β 的基因表达。针对 GSK-3β 的 Western 印迹证实,Pg.LPS(37 kDa 带 p = 0.01)和 A. naeslundii 条件培养基(37 kDa 带 p = 0.001)裂解片段的存在。免疫染色显示了 GSK-3β 在细胞质和细胞核中的定位。因此,Pg.LPS 和来自 A. naeslundii 条件培养基的未知因子通过其具有转录活性的裂解片段介导 GSK-3β 激活。体内的这些毒力因子似乎不利于大脑健康。
{"title":"Porphyromonas gingivalis LPS and Actinomyces naeslundii Conditioned Medium Enhance the Release of a Low Molecular Weight, Transcriptionally Active, Fragment of Glycogen Synthase-3 Kinase in IMR-32 Cell Line","authors":"S. Singhrao, Claudia Consoli, Sarah R. Dennison, S. Kanagasingam, R. Welbury","doi":"10.3233/adr-240066","DOIUrl":"https://doi.org/10.3233/adr-240066","url":null,"abstract":"Background: Glycogen synthase-3 kinase (GSK3) is one of the major contributors of tau hyperphosphorylation linked to neurofibrillary tangles in Alzheimer’s disease (AD). Objective: To determine a mechanism of GSK-3β activation by two periodontal bacteria consistently confirmed in AD autopsied brains. Methods: Porphyromonas gingivalis FDC381 and Actinomyces naeslundii ATCC10301 conditioned media were collected. IMR-32 cells were challenged for 48 h with the conditioned media alongside P. gingivalis (ATCC33277) ultrapurified lipopolysaccharide (LPS) designated Pg.LPS under established cell culture conditions either alone or combined. Gene expression and protein analyses for GSK-3β were carried out. Results: qPCR demonstrated that GSK-3β gene was overexpressed in IMR-32 cells treated with Pg.LPS with a 2.09-fold change (p = 0.0005), while A. naeslundii treated cells demonstrated 1.41-fold change (p = 0.004). Western blotting of the cells challenged with Pg.LPS (p = 0.01) and A. naeslundii conditioned medium (p = 0.001) demonstrated the 37 kDa band for each treatment with variable intensity across the medium control. Immunohistochemistry with the GSK-3β of the IMR-32 cells challenged with Pg.LPS and A. naeslundii alone demonstrated cytoplasmic and nuclear localization. Conclusions: Exposure to various bacterial factors upregulated the gene expression of GSK-3β. Western blotting for GSK-3β confirmed the presence of the cleaved fragment by Pg.LPS (37 kDa band p = 0.01) and A. naeslundii conditioned medium (37 kDa band p = 0.001). Immunostaining demonstrated both cytoplasmic and nuclear localization of GSK-3β. Therefore, Pg.LPS and an unknown factor from the A. naeslundii conditioned medium mediated GSK-3β activation via its transcriptionally active, cleaved, fragment. These virulence factors in the body appear to be detrimental to brain health.","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141827178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}