Journal of Alzheimer's Disease - Volume 94, issue s1

Authors: Satyanarayana, Koneru

Article Type: Other

DOI: 10.3233/JAD-239003

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S1-S1, 2023

Authors: Kosagisharaf, Jagannatha Rao | Hegde, Muralidhar L.

Article Type: Introduction

DOI: 10.3233/JAD-230622

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S3-S7, 2023

Authors: Zhang, Yue | Jia, Jianping

Article Type: Research Article

Abstract: Background: Microglia-driven neuroinflammation has been shown to be involved in the entire process of Alzheimer’s disease (AD). Betaine is a natural product that exhibits anti-inflammatory activity; however, the exact underlying molecular mechanisms are poorly understood. Objective: Our study focused on determining the effect of betaine against amyloid-β42 oligomer (AβO)-induced inflammation in microglial BV2 cells and investigating the underlying mechanism. Methods: AβO was used to establish an in vitro AD model using BV2 cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to measure BV2 cell viability with different concentrations of AβO and betaine. Reverse transcription–polymerase chain …reaction and enzyme-linked immunosorbent assays were used to determine the expression levels of inflammatory factors, such as interleukin-1β (IL-1β), interleukin-18 (IL-18), and tumor necrosis factor α (TNF-α). Western blotting was used to evaluate the activation of the NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome and nuclear transcription factor-κB p65 (NF-κB p65). Moreover, we used phorbol 12-myristate 13-acetate (PMA) to activate NF-κB in order to validate that betaine exerted anti-neuroinflammatory effects through regulation of the NF-κB/NLRP3 signaling pathway. Results: We used 2 mM betaine to treat 5μM AβO-induced microglial inflammation. The administration of betaine effectively decreased the levels of IL-1β, IL-18, and TNF-α without affecting cell viability in BV2 microglial cells. Conclusion: Betaine inhibited AβO-induced neuroinflammation in microglia by inhibiting the activation of the NLRP3 inflammasome and NF-κB, which supports further evaluation of betaine as a potential effective modulator for AD. Show more

Keywords: Alzheimer’s disease, betaine, neuroinflammation, NF-κB, NLRP3

DOI: 10.3233/JAD-230064

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S9-S19, 2023

Authors: Mansor, Nur Izzati | Ling, King-Hwa | Rosli, Rozita | Hassan, Zurina | Adenan, Mohd Ilham | Nordin, Norshariza

Article Type: Research Article

Abstract: Background: Centella asiatica (L.) (C. asiatica ) is commonly known in South East and South East Asia communities for its nutritional and medicinal benefits. Besides being traditionally used to enhance memory and accelerate wound healing, its phytochemicals have been extensively documented for their neuroprotective, neuroregenerative, and antioxidant properties. Objective: The present study aims to investigate the effects of a standardized raw extract of C. asiatica (RECA) on hydrogen peroxide (H2 O2 )-induced oxidative stress and apoptotic death in neural-like cells derived from mouse embryonic stem (ES) cell line. Methods: A transgenic mouse ES …cell (46C) was differentiated into neural-like cells using 4-/4+ protocol with addition of all-trans retinoic acid. These cells were then exposed to H2 O2 for 24 h. The effects of RECA on H2 O2 -induced neural-like cells were assessed through cell viability, apoptosis, and reactive oxygen species (ROS) assays, as well as neurite length measurement. The gene expression levels of neuronal-specific and antioxidant markers were assessed by RT-qPCR analysis. Results: Pre-treatment with H2 O2 for 24 hours, in a dose-dependent manner, damaged neural-like cells as marked by a decrease in cell viability, substantial increase in intracellular ROS accumulation, and increase in apoptotic rate compared to untreated cells. These cells were used to treat with RECA. Treatment with RECA for 48 h remarkably restored cell survival and promoted neurite outgrowth in the H2 O2 - damaged neurons by increasing cell viability and decreasing ROS activity. RT-qPCR analysis revealed that RECA upregulated the level of antioxidant genes such as thioredoxin-1 (Trx-1 ) and heme oxygenase-1 (HO-1 ) of treated cells, as well as the expression level of neuronal-specific markers such as Tuj1 and MAP2 genes, suggesting their contribution in neuritogenic effect. Conclusion: Our findings indicate that RECA promotes neuroregenerative effects and exhibits antioxidant properties, suggesting a valuable synergistic activity of its phytochemical constituents, thus, making the extract a promising candidate in preventing or treating oxidative stress-associated Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, Centella asiatica , mouse embryonic stem cells, oxidative stress, reactive oxygen species

DOI: 10.3233/JAD-221233

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S21-S44, 2023

Authors: Hui, Brendan Su Mee | Zhi, Lee Rui | Retinasamy, Thaarvena | Arulsamy, Alina | Law, Christine Shing Wei | Shaikh, Mohd. Farooq | Yeong, Keng Yoon

Article Type: Systematic Review

Abstract: Background: Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α , which governs various pathological pathways in different NDs. Objective: This systematic review aimed to critically appraise the currently available literature …on the pathological role of IFN-α in neurodegeneration/NDs. Methods: Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search. Results: A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-α may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-α may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production. Conclusion: The exact role IFN-α in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-α . Future investigations should thus be conducted, so that the role played by IFN-α in neurodegenerative diseases could be delineated. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, dementia, HIV-associated neurocognitive disorder, Huntington’s disease, interferon-alpha, multiple sclerosis, Parkinson’s disease

DOI: 10.3233/JAD-221081

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S45-S66, 2023

Authors: Ishabiyi, Felix Oluwasegun | Ogidi, James Okwudirichukwu | Olukade, Baliqis Adejoke | Amorha, Chizoba Christabel | El-Sharkawy, Lina Y. | Okolo, Chukwuemeka Calistus | Adeniyi, Titilope Mary | Atasie, Nkechi Hope | Ibrahim, Abdulwasiu | Balogun, Toheeb Adewale

Article Type: Research Article

Abstract: Background: The development of therapeutic agents against Alzheimer’s disease (AD) has stalled recently. Drug candidates targeting amyloid-β (Aβ) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy. Objective: The study sought to investigate the potential of bioactive compounds derived from Azadirachta-indica to inhibit the NLRP3 protein implicated in the pathophysiology of AD. Methods: Structural bioinformatics via molecular docking and …density functional theory (DFT) analysis was utilized for the identification of novel NLRP3 inhibitors from A. indica bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against that of oridonin, a known NLRP3 inhibitor. Results: The studied compounds optimally saturated the binding site of the NLRP3 NACHT domain, forming principal interactions with the different amino acids at its binding site. The studied compounds also demonstrated better bioactivity and chemical reactivity as ascertained by DFT analysis and all the compounds except 7-desacetyl-7-benzoylazadiradione, which had two violations, conformed to Lipinski’s rule of five. Conclusion: In silico studies show that A. indica derived compounds have better inhibitory potential against NLRP3 and better pharmacokinetic profiles when compared with the reference ligand (oridonin). These compounds are thus proposed as novel NLRP3 inhibitors for the treatment of AD. Further wet-lab studies are needed to confirm the potency of the studied compounds. Show more

Keywords: Alzheimer’s disease, Azadiracta indica, density functional theory, inflammasomes, molecular docking, NLRP3

DOI: 10.3233/JAD-221020

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S67-S85, 2023

Authors: Daly, Timothy | Henry, Vincent | Bourdenx, Mathieu

Article Type: Review Article

Abstract: Background: Many putative causes and risk factors have been associated with outcomes in Alzheimer’s disease (AD) but all attempts at disease-modifying treatment have failed to be clinically significant. Efforts to address this “association—intervention” mismatch have tended to focus on the novel design of interventions. Objective: Here, we instead deal with the notion of association in depth. We introduce the concept of disease-associated process (DAP) as a flexible concept that can unite different areas of study of AD from genetics to epidemiology to identify disease-modifying targets. Methods: We sort DAPs using three properties: specificity for AD, frequency …in patients, and pathogenic intensity for dementia before using a literature review to apply these properties in three ways. Firstly, we describe and visualize known DAPs. Secondly, we exemplify qualitative specificity analysis with the DAPs of tau protein pathology and autophagy to reveal their differential implication in AD. Finally, we use DAP properties to define the terms “risk factor,” “cause,” and “biomarker.” Results: We show how DAPs fit into our collaborative disease ontology, the Alzheimer’s Disease-Associated Processes and Targets (ADAPT) ontology. We argue that our theoretical system can serve as a democratic research forum, offering a more biologically adequate view of dementia than reductionist models. Conclusion: The ADAPT ontology is a tool that could help to ground debates around priority setting using objective criteria for the identifying of targets in AD. Further efforts are needed to address issues of how biomedical research into AD is prioritized and funded. Show more

Keywords: Alzheimer’s disease, association, autophagy, biomarker, cause, disease ontology, intervention, risk factors, specificity, tau

DOI: 10.3233/JAD-221004

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S87-S96, 2023

Authors: Castillo, Carolina | Bravo-Arrepol, Gastón | Wendt, Aline | Saez-Orellana, Francisco | Millar, Camila | Burgos, Carlos F. | Gavilán, Javiera | Pacheco, Carla | Ahumada-Rudolph, Ramón | Napiórkowska, Mariola | Pérez, Claudia | Becerra, José | Fuentealba, Jorge | Cabrera-Pardo, Jaime R.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana …, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects. Objective: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed. Methods: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs. Results: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu. Conclusion: We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents. Show more

Keywords: Aβ interaction, Alzheimer’s disease, amyloid-β peptide, eudesmin, neuroprotection

DOI: 10.3233/JAD-220935

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S97-S108, 2023

Authors: Shirgadwar, Shubhendu M. | Kumar, Rahul | Preeti, Kumari | Khatri, Dharmendra Kumar | Singh, Shashi Bala

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities. Objective: To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axis Methods: The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered …with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α -Synuclein (α -SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1) and autophagic (mTOR, Atg5,7, p62, Beclin,LC3B-I/II) protein activity were evaluated both in in vitro and in vivo . Results: PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, α -SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein. Conclusion: Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management. Show more

Keywords: Apoptosis, autophagy, oxidative stress, Parkinson’s disease, phloretin

DOI: 10.3233/JAD-220793

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S109-S124, 2023

Authors: Surya, Kumar | Manickam, Nivethitha | Jayachandran, Kesavan Swaminathan | Kandasamy, Mahesh | Anusuyadevi, Muthuswamy

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling …have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD. Show more

Keywords: Adult neurogenesis, Alzheimer’s disease, cell cycle, hippocampus, resveratrol, Sirtuin1, Wnt pathway

DOI: 10.3233/JAD-220559

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S125-S140, 2023