Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Zhao, Rangyin | Han, Xiaoyong | Jiang, Shangrong | Zhao, Weijing | Liu, Jia | Zhang, Hongxia | Mao, Xiaoliang | Zhang, Min | Lei, Lili | You, Hong

Article Type: Research Article

Abstract: Background: Dementia is a neuropsychiatric disorder with cognitive decline due to multiple factors. With the arrival of the aging population, the incidence of dementia has gradually increased. There is still no effective treatment for dementia, and therefore, the prevention of dementia has become crucial. Oxidative stress is considered to be one of the pathogenesis of dementia; therefore, antioxidant therapy and prevention of dementia have been gradually proposed. Objective: Our meta-analysis aimed to investigate the association of antioxidants with risk of dementia. Methods: We searched PubMed, Embase, and Web of Science databases for articles on antioxidants associated …with dementia risk, and those containing cohort studies with high-dose versus low-dose controls were included in our meta-analysis. The resulting risk ratios (RR) and hazard ratios (HR) and 95% confidence intervals were statistically analyzed using Stata12.0 free software. Results: A total of 17 articles were included in this meta-analysis. Of 98,264 participants, 7,425 had dementia after 3–23 years of follow-up. The results of the meta-analysis showed a trend towards a lower incidence of dementia with high intake of antioxidants (RR = 0.84, 95% CI 0.77–1.19 I 2  = 54.6%), but this was not statistically significant. High antioxidant intake significantly reduced the incidence of Alzheimer ‘s disease (RR = 0.85, 95% CI 0.79–0.92 I 2  = 45.5%), and we additionally carried out subgroup analyses by nutrient type, diet or supplement, region, and study quality score. Conclusion: Dietary intake of antioxidants or supplements reduces both the risk of dementia and the risk of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, antioxidants, dementia, meta-analysis, risk

DOI: 10.3233/JAD-220909

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Soto-Mercado, Viviana | Mendivil-Perez, Miguel | Velez-Pardo, Carlos | Jimenez-Del-Rio, Marlene

Article Type: Research Article

Abstract: Background: Familial Alzheimer’s disease (FAD) is caused by mutations in one or more of 3 genes known as A β PP , PSEN1 , and PSEN2 . There are currently no effective therapies for FAD. Hence, novel therapeutics are needed. Objective: To analyze the effect of treatment with a combination of epigallocatechin-3-gallate (EGCG) and Melatonin (N-acetyl-5-methoxytryptamine, aMT) in a cerebral spheroid (CS) 3D in vitro model of PSEN 1 E280A FAD. Methods: We developed a CS in vitro model based on menstrual stromal cells derived from wild-type (WT) and mutant PSEN1 E280A …menstrual blood cultured in Fast-N-Spheres V2 medium. Results: Beta-tubulin III, choline acetyltransferase, and GFAP in both WT and mutant CSs spontaneously expressed neuronal and astroglia markers when grown in Fast-N-Spheres V2 medium for 4 or 11 days. Mutant PSEN1 CSs had significantly increased levels of intracellular AβPP fragment peptides and concomitant appearance of oxidized DJ-1 as early as 4 days, and phosphorylated tau, decreased ΔΨ m , and increased caspase-3 activity were observed on Day 11. Moreover, mutant CSs were unresponsive to acetylcholine. Treatment with a combination of EGCG and aMT decreased the levels of all typical pathological markers of FAD more efficiently than did EGCG or aMT alone, but aMT failed to restore Ca2 + influx in mutant CSs and decreased the beneficial effect of EGCG on Ca2 + influx in mutant CSs. Conclusion: Treatment with a combination of EGCG and aMT can be of high therapeutic value due to the high antioxidant capacity and anti-amyloidogenic effect of both compounds. Show more

Keywords: Alzheimer’s disease, cerebral spheroids, E280A, -(–) epigallocatechin 3-gallate, melatonin, menstrual mesenchymal stromal cell, mutation, presenilin

DOI: 10.3233/JAD-220903

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Zhou, Moran | Jiao, Qian | Wu, Zengrui | Li, Weihua | Liu, Guixia | Wang, Rui | Tang, Yun

Article Type: Research Article

Abstract: Background: The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ ) in the field of understanding the mechanisms of Alzheimer’s disease (AD), a complicated and untreatable neurodegenerative disease. Objective: The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms. Methods: In this study, a systematic workflow combining pharmacological experiments and computational prediction were proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data …on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation. Results: 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan. Conclusion: Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD. Show more

Keywords: Alzheimer’s disease, computational systems pharmacology, oxidative stress hypothesis, phenotypic screening, polypharmacology networks, therapeutic targets

DOI: 10.3233/JAD-220727

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023

Authors: Yang, Lei | Zhao, Fengxue | Sun, Yadi | Wang, Ziyi | Li, Qianwen | Wang, Hao | Lu, Ying

Article Type: Systematic Review

Abstract: Background: Mild cognitive impairment (MCI) is the prodromal stage of dementia. In this stage, reasonable intervention measures can help to delay the decline of cognitive function. Supplementation of n-3 polyunsaturated fatty acids (n-3PUFAs) may be beneficial to delay the decline of cognitive function in the elderly. Objective: To investigate the effectiveness of docosapentaenoic acid (DHA) or/and eicosapentaenoic acid (EPA) supplements in the elderly with MCI. Methods: Eight electronic databases, PubMed, Cochrane Library, Embase, VIP, SinoMed, Web of Science, CNKI, and WANFANG DATA, were searched for related articles from inception until January 2022. Subgroup analyses and sensitivity …analyses were performed to detect confounding variables. Standardized mean differences (SMD) with 95% confidence intervals (CI) were determined. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots. Stata12.0 was used for Begg’s and Egger’s test to quantify whether publication bias. Linear relationship between global cognition and covariates was examined in meta-regression analysis. Results: Twelve studies (n  = 1,124) were included. The methodological quality of research is mostly medium. Compared with placebo, n-3PUFAs supplements have benefits on global cognition [SMD = 0.51, 95% CI(0.12, 0.91), p  = 0.01]. No significant differences were observed between intervention group and placebo on language fluency, executive functions, and depression. Conclusion: Our findings indicated DHA and/or EPA supplements have benefits on global cognition, and it may also reduce the level of blood amyloid-β (Aβ)-related biomarkers (e.g., Aβ 40 , Aβ 42 ) and inflammatory factors (e.g., 1L-6, 1L-10). Since there are only two relative articles, more research is needed in the future to clarify the relationship. Show more

Keywords: Elderly, meta-analysis, mild cognitive impairment, n-3 polyunsaturated fatty acids

DOI: 10.3233/JAD-220863

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: Bian, Zhihong | Yu, Haibo | Hu, Xinran | Bian, Yuting | Sun, Hongming | Tadokoro, Koh | Takemoto, Mami | Yunoki, Taijun | Nakano, Yumiko | Fukui, Yusuke | Morihara, Ryuta | Abe, Koji | Yamashita, Toru

Article Type: Research Article

Abstract: Background: NADPH oxidase 2 (NOX2) is an important source of reactive oxygen species (ROS). Activated NOX2 may contribute to Alzheimer’s disease (AD). Our previous studies showed that a novel vitamin E mixture, Tocovid, had potential neuroprotective effects in a stroke mice model and an AD cell model. Objective: The aim of this study was two-fold: to assess whether long-term Tocovid treatment can regulate NOX2, and the therapeutic effects of long-term administration of Tocovid to an AD mice model. Methods: Therapeutic effects of long-term administration of Tocovid (200 mg/kg /day) on an Aβ-overexpressed transgenic AD mice model (APP23, …n  = 8) was investigated. The therapeutic effect of Tocovid in 16-month-old mice compared with the no-treatment APP23 group (n  = 9) was assessed. Results: Tocovid treatment strongly improved motor and memory deficits of APP23 mice by attenuating NOX2 expression, oxidative stress, neuroinflammation, neurovascular unit dysfunction, synaptic alteration, and Aβ deposition after 16 months. Conclusion: These findings suggest that NOX2 is a potential target in AD pathology. Long-term administration of Tocovid may be a promising candidate for AD treatment. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, NOX2, oxidative stress, Tocovid

DOI: 10.3233/JAD-220761

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Liang, Jingjing | LaFleur, Bonnie | Hussainy, Sadiya | Perry, George

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly marked by central nervous system (CNS) neuronal loss and amyloid plaques. FAM222A , encoding an amyloid plaque core protein, is an AD brain atrophy susceptibility gene that mediates amyloid-β aggregation. However, the expression interplay between FAM222A and other AD-related pathway genes is unclear. Objective: Our goal was to study FAM222A ’s whole-genome co-expression profile in multiple tissues and investigate its interplay with other AD-related genes. Methods: We analyzed gene expression correlations in Genotype-Tissue Expression (GTEx) tissues to identify FAM222A co-expressed …genes and performed functional enrichment analysis on identified genes in CNS system. Results: Genome-wide gene expression profiling identified 673 genes significantly correlated with FAM222A (p  <  2.5×10–6 ) in 48 human tissues, including 298 from 13 CNS tissues. Functional enrichment analysis revealed that FAM222A co-expressed CNS genes were enriched in multiple AD-related pathways. Gene co-expression network analysis for identified genes in each brain region predicted other disease associated genes with similar biological function. Furthermore, co-expression of 25 out of 31 AD-related pathways genes with FAM222A was replicated in brain samples from 107 aged subjects from the Aging, Dementia and TBI Study. Conclusion: This gene co-expression study identified multiple AD-related genes that are associated with FAM222A , indicating that FAM222A and AD-associated genes can be active simultaneously in similar biological processes, providing evidence that supports the association of FAM222A with AD. Show more

Keywords: Alzheimer’s disease, FAM222A, gene co-expression network analysis, neurodegeneration, transcriptomics

DOI: 10.3233/JAD-221241

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: Puoyan-Majd, Samira | Parnow, Abdolhossein | Rashno, Masome | Heidarimoghadam, Rashid | Komaki, Alireza

Article Type: Research Article

Abstract: Background: Oxidative stress plays a major role in the progression of Alzheimer’s disease (AD)-related cognitive deficits. Objective: This study was done to determine the protective effects of coenzyme Q10 (CoQ10) and high-intensity interval training (HIIT) alone and in combination for eight continuous weeks, on oxidative status, cognitive functions, and histological changes in the hippocampus in amyloid-β (Aβ)-induced AD rats. Methods: Ninety male Wistar rats were randomly assigned to the sham, control, Q10 (50 mg/kg of CoQ10; P.O.), HIIT (high intensity: 4 min running at 85–90% VO2max, low intensity: 3 min running at 50–60% VO2max), Q10 + HIIT, AD, AD+Q10, AD+HIIT, and …AD+Q10 + HIIT groups. Results: The results showed that Aβ injection reduced cognitive functions in the Morris water maze (MWM) test and recognition memory in the novel object recognition test (NORT), which was accompanied by a decrease in total thiol groups, catalase, and glutathione peroxidase activities, an increase in malondialdehyde levels, and neuronal loss in the hippocampus. Interestingly, pretreatment with CoQ10, HIIT, or both, could markedly improve the oxidative status and cognitive decline in the MWM and NOR tests, and hinder neuronal loss in the hippocampus of Aβ-induced AD rats. Conclusion: Therefore, a combination of CoQ10 and HIIT can improve Aβ-related cognitive deficits, probably through an amelioration in hippocampal oxidative status and prevention of neuronal loss. Show more

Keywords: Alzheimer’s disease, coenzyme Q10, high-intensity interval training, Morris water maze, novel object recognition test, oxidative status, rat

DOI: 10.3233/JAD-230096

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Yan, Ran | Wang, Wenjing | Yang, Wen | Huang, Masha | Xu, Wei

Article Type: Research Article

Abstract: Background: Late-onset Alzheimer’s disease (LOAD) is the most common type of dementia, but its pathogenesis remains unclear, and there is a lack of simple and convenient early diagnostic markers to predict the occurrence. Objective: Our study aimed to identify diagnostic candidate genes to predict LOAD by machine learning methods. Methods: Three publicly available datasets from the Gene Expression Omnibus (GEO) database containing peripheral blood gene expression data for LOAD, mild cognitive impairment (MCI), and controls (CN) were downloaded. Differential expression analysis, the least absolute shrinkage and selection operator (LASSO), and support vector machine recursive feature elimination …(SVM-RFE) were used to identify LOAD diagnostic candidate genes. These candidate genes were then validated in the dataset validation group and clinical samples, and a LOAD prediction model was established. Results: LASSO and SVM-RFE analyses identified 3 mitochondria-related genes (MRGs) as candidate genes, including NDUFA1, NDUFS5, and NDUFB3. In the verification of 3 MRGs, the AUC values showed that NDUFA1 , NDUFS5 had better predictability. We also verified the candidate MRGs in MCI groups, the AUC values showed a good performance. We then used NDUFA1, NDUFS5 and age to build a LOAD diagnostic model and AUC was 0.723. Results of qRT-PCR experiments showed that the three candidate genes were expressed significantly lower in the LOAD and MCI groups when compared to CN. Conclusion: Two mitochondrial-related candidate genes, NDUFA1 and NDUFS5, were identified as diagnostic markers for LOAD and MCI. Combining these two candidate genes with age, a LOAD diagnostic prediction model was successfully constructed. Show more

Keywords: Alzheimer’s disease, biomarker, late-onset Alzheimer’s disease, immune cells, machine learning, mild cognitive impairment, mitochondria related genes

DOI: 10.3233/JAD-230314

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2023

Authors: Daly, Timothy

Article Type: Review Article

Abstract: Maintaining diversity in drug development in research into Alzheimer’s disease (AD) is necessary to avoid over-reliance on targeting AD neuropathology. Treatments that reduce or prevent the generation of oxidative stress, frequently cited for its causal role in the aging process and AD, could be useful in at-risk populations or diagnosed AD patients. However, in this review, it is argued that clinical research into antioxidants in AD could provide more useful feedback as to the therapeutic value of the oxidative stress theory of AD. Improving comparability between randomized controlled trials (RCTs) is vital from a waste-reduction and priority-setting point of view …for AD clinical research. For as well as attempting to improve meaningful outcomes for patients, RCTs of antioxidants in AD should strive to maximize the extraction of clinically useful information and actionable feedback from trial outcomes. Solutions to maximize information flow from RCTs of antioxidants in AD are offered here in the form of checklist questions to improve ongoing and future trials centered around the following dimensions: adhesion to reporting guidelines like CONSORT, biomarker enrichment, simple tests of treatment, and innovative trial design. Show more

Keywords: Alzheimer’s disease, antioxidants, biomarkers, clinical trials, drug pipeline, information flow, oxidative stress, standardization, trial innovation

DOI: 10.3233/JAD-230308

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Huang, Yiyao | Driedonks, Tom A.P. | Cheng, Lesley | Turchinovich, Andrey | Pletniková, Olga | Redding-Ochoa, Javier | Troncoso, Juan C. | Hill, Andrew F. | Mahairaki, Vasiliki | Zheng, Lei | Witwer, Kenneth W.

Article Type: Research Article

Abstract: Background: Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer’s disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. Objective: This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. Methods: bdEVs from age-matched late-stage AD patients (n  = 23) and controls (n  = 10) …that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. Results: Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. Conclusions: Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis. Show more

Keywords: Alzheimer’s disease, brain, ectosomes, exosomes, extracellular vesicles, microvesicles, miRNAs, non-coding RNAs, RNA sequencing, tRNAs

DOI: 10.3233/JAD-230872

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023