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

Authors: Li, Dun | Yang, Hongxi | Lyu, Mingqian | Wang, Ju | Xu, Weili | Wang, Yaogang

Article Type: Research Article

Abstract: Background: Dementia, mainly Alzheimer’s disease (AD) and vascular dementia (VaD), remains a global health challenge. Previous studies have demonstrated the benefits of acupuncture therapy (AT) in improving dementia. Nevertheless, the therapeutic targets and integrated biological mechanisms involved remain ambiguous. Objective: To identify therapeutic targets and biological mechanisms of AT in treating dementia by integrated analysis strategy. Methods: By the identification of differentially expressed genes (DEGs) of AD, VaD, and molecular targets of AT active components, the acupuncture therapeutic targets associated with the biological response to AD and VaD were extracted. Therapeutic targets-based functional enrichment analysis was …conducted, and multiple networks were constructed. AT-therapeutic crucial targets were captured by weighted gene co-expression network analysis (WGCNA). The interactions between crucial targets with AT active components were verified by molecular docking. Results: Our results demonstrated that 132 and 76 acupuncture therapeutic targets were associated with AD and VaD. AT-therapeutic crucial targets including 58 for AD and 24 for VaD were captured by WGCNA, with 11 in shared, including NMU , GRP , TAC1 , ADRA1D , and SST . In addition, 35 and 14 signaling pathways were significantly enriched by functional enrichment analysis, with 6 mutual pathways including neuroactive ligand-receptor interaction, GABAergic synapse, calcium signaling pathway, cAMP signaling pathway, chemokine signaling pathway, and inflammatory mediator regulation of TRP channels. Conclusion: The improvement of AD and VaD by AT was associated with modulation of synaptic function, immunity, inflammation, and apoptosis. Our study clarified the therapeutic targets of AT on dementia, providing valuable clues for complementing and combining pharmacotherapy. Show more

Keywords: Acupuncture, Alzheimer’s disease, dementia, vascular dementia

DOI: 10.3233/JAD-221018

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S141-S158, 2023

Authors: Yeap, Yee Jie | Kandiah, Nagaendran | Nizetic, Dean | Lim, Kah-Leong

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given …this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor secretase, beta-secretase, neuroprotection

DOI: 10.3233/JAD-220867

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S159-S171, 2023

Authors: Chen, Xiaokun | Jiang, Shenzhong | Wang, Renzhi | Bao, Xinjie | Li, Yongning

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), a progressive dementia, is one of the world’s most dangerous and debilitating diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Further understanding of the mechanisms underlying AD and the development of novel therapeutic options are critical. Neurogenesis is impaired in AD, which contributes to memory deficits. Transplanted neural stem cells (NSCs) can regenerate degraded cholinergic neurons, and new neurons derived from NSCs can form synaptic connections with neighboring neurons. In theory, …employing NSCs to replace and restore damaged cholinergic neurons and brain connections may offer new treatment options for AD. However there remain barriers to surmount before NSC-based therapy can be used clinically. The objective of this article is to describe recent advances in the treatment of AD models and clinical trials involving NSCs. In addition, we discuss the challenges and prospects associated with cell transplant therapy for AD. Show more

Keywords: Alzheimer’s disease, cell therapy, neural stem cells, neurodegenerative disease, transplantation

DOI: 10.3233/JAD-220721

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S173-S186, 2023

Authors: Tryphena, Kamatham Pushpa | Anuradha, Urati | Kumar, Rohith | Rajan, Shruti | Srivastava, Saurabh | Singh, Shashi Bala | Khatri, Dharmendra Kumar

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting the elderly worldwide and causing significant movement impairments. The goal of PD treatment is to restore dopamine levels in the striatum and regulate movement symptoms. The lack of specific biomarkers for early diagnosis, as well as medication aimed at addressing the pathogenic mechanisms to decelerate the progression of dopaminergic neurodegeneration, are key roadblocks in the management of PD. Various pathogenic processes have been identified to be involved in the progression of PD, with mitochondrial dysfunction being a major contributor to the disease’s pathogenesis. The regulation of mitochondrial functions is …influenced by a variety of factors, including epigenetics. microRNAs (miRNAs) are epigenetic modulators involved in the regulation of gene expression and regulate a variety of proteins that essential for proper mitochondrial functioning. They are found to be dysregulated in PD, as evidenced by biological samples from PD patients and in vitro and in vivo research. In this article, we attempt to provide an overview of several miRNAs linked to mitochondrial dysfunction and their potential as diagnostic biomarkers and therapeutic targets in PD. Show more

Keywords: Biomarkers, microRNA, mitochondrial dysfunction, Parkinson’s disease

DOI: 10.3233/JAD-220449

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S187-S202, 2023

Authors: Elzayat, Emad M. | Shahien, Sherif A. | El-Sherif, Ahmed A. | Hosney, Mohamed

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a cumulative progressive neurodegenerative disease characterized mainly by impairment in cognitive functions accompanied by memory loss, disturbance in behavior and personality, and difficulties in learning. Although the main causes of AD pathogenesis are not fully understood yet, amyloid-β peptides and tau proteins are supposed to be responsible for AD onset and pathogenesis. Various demographic, genetic, and environmental risk factors are involved in AD onset and pathogenesis such as age, gender, several genes, lipids, malnutrition, and poor diet. Significant changes were observed in microRNA (miRNA) levels between normal and AD cases giving hope for a diagnostic procedure …for AD through a simple blood test. As yet, only two classes of AD therapeutic drugs are approved by FDA. They are classified as acetylcholinesterase inhibitors and N-methyl-D-aspartate antagonists (NMDA). Unfortunately, they can only treat the symptoms but cannot cure AD or stop its progression. New therapeutic approaches were developed for AD treatment including acitretin due to its ability to cross blood-brain barrier in the brain of rats and mice and induce the expression of ADAM 10 gene, the α-secretase of human amyloid-β protein precursor, stimulating the non-amyloidogenic pathway for amyloid-β protein precursor processing resulting in amyloid-β reduction. Also stem cells may have a crucial role in AD treatment as they can improve cognitive functions and memory in AD rats through regeneration of damaged neurons. This review spotlights on promising diagnostic techniques such as miRNAs and therapeutic approaches such as acitretin and/or stem cells keeping in consideration AD pathogenesis, stages, symptoms, and risk factors. Show more

Keywords: Acitretin, Alzheimer’s disease, amyloid-β peptide, miRNA, pathogenesis, risk factors, tau proteins, stem cells

DOI: 10.3233/JAD-221298

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S203-S225, 2023

Authors: Huang, Li | Lu, Zhaogang | Zhang, Hexin | Wen, Hongyong | Li, Zongji | Liu, Qibing | Wang, Rui

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide. The accumulation of amyloid-β (Aβ) protein and plaque formation in the brain are two major causes of AD. Interestingly, growing evidence demonstrates that the gut flora can alleviate AD by affecting amyloid production and metabolism. However, the underlying mechanism remains largely unknown. This review will discuss the possible association between the gut flora and Aβ in an attempt to provide novel therapeutic directions for AD treatment based on the regulatory effect of Aβ on the gut flora.

Keywords: Alzheimer’s disease, amyloid-β, colitis, insulin resistance, intestinal flora, neuroinflammation

DOI: 10.3233/JAD-220651

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S227-S239, 2023

Authors: Raghavan, Kadalraja | Dedeepiya, Vidyasagar Devaprasad | Yamamoto, Naoki | Ikewaki, Nobunao | Sonoda, Tohru | Iwasaki, Masaru | Kandaswamy, Ramesh Shankar | Senthilkumar, Rajappa | Preethy, Senthilkumar | Abraham, Samuel J.K.

Article Type: Research Article

Abstract: Background: Aureobasidium pullulans (black yeast) AFO-202 strain-produced beta glucan, Nichi Glucan, has been shown to improve the behavior and sleep pattern along with an increase in α-synuclein and melatonin in children with autism spectrum disorder (ASD). Objective: In this randomized pilot clinical study, we have evaluated the gut microbiota of subjects with ASD after consumption of Nichi Glucan. Methods: Eighteen subjects with ASD were randomly allocated: six subjects in the control group (Group 1): conventional treatment comprising remedial behavioral therapies and L-carnosine 500 mg per day, and 12 subjects (Group 2) underwent supplementation with Nichi Glucan …0.5 g twice daily along with the conventional treatment for 90 days. Results: Whole genome metagenome (WGM) sequencing of the stool samples at baseline and after intervention showed that among genera of relevance, the abundance of Enterobacteriaceae was decreased almost to zero in Group 2 after intervention, whereas it increased from 0.36% to 0.85% in Group 1. The abundance of Bacteroides increased in Group 1, whereas it decreased in Group 2. The abundance of Prevotella increased while the abundance of Lactobacillus decreased in both Group 1 and Group 2. Among species, a decrease was seen in Escherichia coli , Akkermansia muciniphila CAG:154 , Blautia spp. , Coprobacillus sp. , and Clostridium bolteae CAG:59 , with an increase of Faecalibacterium prausnitzii and Prevotella copri , which are both beneficial. Conclusion: AFO-202 beta 1,3–1,6 glucan, in addition to balancing the gut microbiome in children with ASD and its role in effective control of curli-producing Enterobacteriaceae that leads to α-synuclein misfolding and accumulation, may have a prophylactic role in Parkinson’s and Alzheimer’s diseases as well. Show more

Keywords: AFO-202, autism, beta glucans, curli protein, Enterobacteriaceae, neurodegenerative diseases

DOI: 10.3233/JAD-220388

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S241-S252, 2023

Authors: Liew, Yee | Retinasamy, Thaarvena | Arulsamy, Alina | Ali, Idrish | Jones, Nigel C. | O’Brien, Terence J. | Shaikh, Mohd Farooq

Article Type: Systematic Review

Abstract: Background: Neuroinflammation is an innate immunological response of the central nervous system that may be induced by a brain insult and chronic neurodegenerative conditions. Recent research has shown that neuroinflammation may contribute to the initiation of Alzheimer’s disease (AD) pathogenesis and associated epileptogenesis. Objective: This systematic review aimed to investigate the available literature on the shared molecular mechanisms of neuroinflammation in AD and epilepsy. Methods: The search included in this systematic review was obtained from 5 established databases. A total of 2,760 articles were screened according to inclusion criteria. Articles related to the modulation of the …inflammatory biomarkers commonly associated with the progression of AD and epilepsy in all populations were included in this review. Results: Only 7 articles met these criteria and were chosen for further analysis. Selected studies include both in vitro and in vivo research conducted on rodents. Several neuroinflammatory biomarkers were reported to be involved in the cross-talk between AD and epilepsy. Conclusion: Neuroinflammation was directly associated with the advancement of AD and epilepsy in populations compared to those with either AD or epilepsy. However, more studies focusing on common inflammatory biomarkers are required to develop standardized monitoring guidelines to prevent the manifestation of epilepsy and delay the progression of AD in patients. Show more

Keywords: Alzheimer’s disease, epilepsy, epileptogenesis, neurodegeneration, neuroinflammation, neuropathology

DOI: 10.3233/JAD-230059

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S253-S265, 2023

Authors: Zhao, Yan | Zhang, Yizhou | Meng, Sijia | Chen, Bingyu | Dong, Xinyi | Guo, Xiaojing | Guo, Fangzhen | Zhang, Runjiao | Cui, Huixian | Li, Sha

Article Type: Systematic Review

Abstract: Background: There is increasing evidence that supplementation of S-adenosylmethionine (SAM) can improve cognitive function in animals and humans, although the outcomes are not always inconsistent. Objective: We conducted a systematic review and meta-analysis to evaluate the correlation between SAM supplementation and improved cognitive function. Methods: We searched studies in the PubMed, Cochrane Library, Embase, Web of Science, and Clinical Trials databases from January 1, 2002 to January 1, 2022. Risk of bias was assessed using the Cochrane risk of bias 2.0 (human studies) and the Systematic Review Center for Laboratory Animal Experimentation risk of bias (animal …studies) tools; and evidence quality was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation. STATA software was employed to perform meta-analysis, and the random-effects models was used to evaluate the standardized mean difference with 95% confidence intervals. Results: Out of the 2,375 studies screened, 30 studies met the inclusion criteria. Meta-analyses of animal (p  = 0.213) and human (p  = 0.047) studies showed that there were no significant differences between the SAM supplementation and control groups. The results of the subgroup analyses showed that the animals aged ≤8 weeks (p  = 0.027) and the intervention duration >8 weeks (p  = 0.009) were significantly different compared to the controls. Additionally, the Morris water maze test (p  = 0.005) used to assess the cognitive level of the animals revealed that SAM could enhance spatial learning and memory in animals. Conclusion: SAM supplementation showed no significant improvement in cognition. Therefore, further studies are needed to assess the effectiveness of SAM supplementation. Show more

Keywords: Cognition, meta-analyses, Morris water maze test, randomized controlled trials, S-adenosylmethionine

DOI: 10.3233/JAD-221076

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S267-S287, 2023

Authors: Roshan, Syed Aasish | Elangovan, Gayathri | Gunaseelan, Dharani | Jayachandran, Swaminathan K. | Kandasamy, Mahesh | Anusuyadevi, Muthuswamy

Article Type: Research Article

Abstract: Background: Cerebral ischemic stroke is caused due to neurovascular damage or thrombosis, leading to neuronal dysfunction, neuroinflammation, neurodegeneration, and regenerative failure responsible for neurological deficits and dementia. The valid therapeutic targets against cerebral stroke remain obscure. Thus, insight into neuropathomechanisms resulting from the aberrant expression of genes appears to be crucial. Objective: In this study, we have elucidated how neurogenesis-related genes are altered in experimental stroke brains from the available transcriptome profiles in correlation with transcriptome profiles of human postmortem stroke brain tissues. Methods: The transcriptome datasets available on the middle cerebral artery occlusion (MCAo) rat …brains were obtained from the Gene Expression Omnibus, National Center for Biotechnology Information. Of the available datasets, 97 samples were subjected to the meta-analysis using the network analyst tool followed by Cytoscape-based enrichment mapping analysis. The key differentially expressed genes (DEGs) were validated and compared with transcriptome profiling of human stroke brains. Results: Results revealed 939 genes are differently expressed in the brains of the MCAo rat model of stroke, in which 30 genes are key markers of neural stem cells, and regulators of neurogenic processes. Its convergence with DEGs from human stroke brains has revealed common targets. Conclusion: This study has established a panel of highly important DEGs to signify the potential therapeutic targets for neuroregenerative strategy against pathogenic events associated with cerebral stroke. The outcome of the findings can be translated to mitigate neuroregeneration failure seen in various neurological and metabolic disease manifestations with neurocognitive impairments. Show more

Keywords: Dementia, meta-analysis, microarray, middle cerebral artery occlusion, neurogenesis, stroke, transcriptome

DOI: 10.3233/JAD-220831

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S289-S308, 2023

Authors: Li, Tianqi | Pappas, Colleen | Klinedinst, Brandon | Pollpeter, Amy | Larsen, Brittany | Hoth, Nathan | Anton, Faith | Wang, Qian | Willette, Auriel A.

Article Type: Research Article

Abstract: Background: Insulin-like growth factor (IGF)-1 plays an important role in Alzheimer’s disease (AD) pathogenesis and increases disease risk. However, prior research examining IGF-1 levels and brain neural network activity is mixed. Objective: The present study investigated the relationship between IGF-1 levels and 21 neural networks, as measured by functional magnetic resonance imaging (fMRI) in 13,235 UK Biobank participants. Methods: Linear mixed models were used to regress IGF-1 against the intrinsic functional connectivity (i.e., degree of network activity) for each neural network. Interactions between IGF-1 and AD risk factors such as Apolipoprotein E4 (APOE4 ) genotype, sex, …AD family history, and age were also tested. Results: Higher IGF-1 was associated with more network activity in the right Executive Function neural network. IGF-1 interactions with APOE4 or sex implicated motor, primary/extrastriate visual, and executive function related neural networks. Neural network activity trends with increasing IGF-1 were different in different age groups. Higher IGF-1 levels relate to much more network activity in the Sensorimotor Network and Cerebellum Network in early-life participants (40–52 years old), compared with mid-life (52–59 years old) and late-life (59–70 years old) participants. Conclusion: These findings suggest that sex and APOE4 genotype may modify the relationship between IGF-1 and brain network activities related to visual, motor, and cognitive processing. Additionally, IGF-1 may have an age-dependent effect on neural network connectivity. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, functional MRI, insulin-like growth factor-1

DOI: 10.3233/JAD-220608

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S309-S318, 2023

Authors: Basha, SK Chand | Ramaiah, Mekala Janaki | Kosagisharaf, Jagannatha Rao

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-β (Aβ), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aβ is one of the physiological roles of TREM2, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by …impairing TREM2–Aβ binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aβ phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aβ clearance. We indicate that TREM2 has the potential to ameliorate the Aβ burden, though with differential clearance ability and may act as a potential therapeutic target. Show more

Keywords: Alzheimer’s disease, amyloid-β, DAP10, DAP12, disease associated microglia, microglia, neurodegeneration, PLCγ2, DAM, R47H, TREM2

DOI: 10.3233/JAD-221070

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S319-S333, 2023

Authors: Huang, Wenhao | Xia, Qing | Zheng, Feifei | Zhao, Xue | Ge, Fangliang | Xiao, Jiaying | Liu, Zijie | Shen, Yingying | Ye, Ke | Wang, Dayong | Li, Yanze

Article Type: Review Article

Abstract: The neurovascular unit (NVU) is involved in the pathological changes in Alzheimer’s disease (AD). The NVU is a structural and functional complex that maintains microenvironmental homeostasis and metabolic balance in the central nervous system. As one of the most important components of the NVU, microglia not only induce blood-brain barrier breakdown by promoting neuroinflammation, the infiltration of peripheral white blood cells and oxidative stress but also mediate neurovascular uncoupling by inducing mitochondrial dysfunction in neurons, abnormal contraction of cerebral vessels, and pericyte loss in AD. In addition, microglia-mediated dysfunction of cellular components in the NVU, such as astrocytes and pericytes, …can destroy the integrity of the NVU and lead to NVU impairment. Therefore, we review the mechanisms of microglia-mediated NVU dysfunction in AD. Furthermore, existing therapeutic advancements aimed at restoring the function of microglia and the NVU in AD are discussed. Finally, we predict the role of pericytes in microglia-mediated NVU dysfunction in AD is the hotspot in the future. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, microglia, neurovascular uncoupling, neurovascular unit, pericyte

DOI: 10.3233/JAD-221064

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S335-S354, 2023

Authors: Guo, Xiaodi | Zhang, Guoxin | Peng, Qinyu | Huang, Liqin | Zhang, Zhaohui | Zhang, Zhentao

Article Type: Review Article

Abstract: Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer’s disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating …neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, Apolipoprotein E4, meningeal lymphatic vessels, tau

DOI: 10.3233/JAD-221016

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S355-S366, 2023

Authors: Zhang, Ruxin | Song, Yanrong | Su, Xuefeng

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is considered to be the most common neurodegenerative disease, with clinical symptoms encompassing progressive memory loss and cognitive impairment. Necroptosis is a form of programmed necrosis that promotes cell death and neuroinflammation, which further mediates the pathogenesis of several neurodegenerative diseases, especially AD. Current evidence has strongly suggested that necroptosis is activated in AD brains, resulting in neuronal death and cognitive impairment. We searched the PubMed database, screening all articles published before September 28, 2022 related to necroptosis in the context of AD pathology. The keywords in the search included: “necroptosis”, “Alzheimer’s disease”, “signaling pathways”, “Aβ”, Aβo”, …“Tau”, “p-Tau”, “neuronal death”, “BBB damage”, “neuroinflammation”, “microglia”, “mitochondrial dysfunction”, “granulovacuolar degeneration”, “synaptic loss”, “axonal degeneration”, “Nec-1”, “Nec-1s”, “GSK872”, “NSA”, “OGA”, “RIPK1”, “RIPK3”, and “MLKL”. Results show that necroptosis has been involved in multiple pathological processes of AD, including amyloid-β aggregation, Tau accumulation, neuronal death, and blood-brain barrier damage, etc. More importantly, existing research on AD necroptosis interventions, including drug intervention and potential gene targets, as well as its current clinical development status, was discussed. Finally, the issues pertaining to necroptosis in AD were presented. Accordingly, this review may provide further insight into clinical perspectives and challenges for the future treatment of AD by targeting the necroptosis pathway. Show more

Keywords: Alzheimer’s disease, granulovacuolar degeneration, mitochondrial dysfunction, MLKL, necroptosis, neurodegeneration, neuronal death, RIPK1, RIPK3

DOI: 10.3233/JAD-220809

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S367-S386, 2023

Authors: Krishna, Geethu | Santhoshkumar, Rashmi | Sivakumar, Palanimuthu Thangaraju | Alladi, Suvarna | Mahadevan, Anita | Dahale, Ajit B. | Arshad, Faheem | Subramanian, Sarada

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. Objective: To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. Methods: Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized …using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. Results: The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. Conclusion: Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD. Show more

Keywords: Alzheimer’s disease, exosomes, frontotemporal dementia, golgin A4, immunoblotting, LAMP-2, MFN-2, neurogranin

DOI: 10.3233/JAD-220829

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S387-S397, 2023

Authors: Naren, Padmashri | Cholkar, Anjali | Kamble, Suchita | Khan, Sabiya Samim | Srivastava, Saurabh | Madan, Jitender | Mehra, Neelesh | Tiwari, Vinod | Singh, Shashi Bala | Khatri, Dharmendra Kumar

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative illness majorly affecting the population between the ages of 55 to 65 years. Progressive dopaminergic neuronal loss and the collective assemblage of misfolded alpha-synuclein in the substantia nigra, remain notable neuro-pathological hallmarks of the disease. Multitudes of mechanistic pathways have been proposed in attempts to unravel the pathogenesis of PD but still, it remains elusive. The convergence of PD pathology is found in organelle dysfunction where mitochondria remain a major contributor. Mitochondrial processes like bioenergetics, mitochondrial dynamics, and mitophagy are under strict regulation by the mitochondrial genome and nuclear genome. These …processes aggravate neurodegenerative activities upon alteration through neuroinflammation, oxidative damage, apoptosis, and proteostatic stress. Therefore, the mitochondria have grabbed a central position in the patho-mechanistic exploration of neurodegenerative diseases like PD. The management of PD remains a challenge to physicians to date, due to the variable therapeutic response of patients and the limitation of conventional chemical agents which only offer symptomatic relief with minimal to no disease-modifying effect. This review describes the patho-mechanistic pathways involved in PD not only limited to protein dyshomeostasis and oxidative stress, but explicit attention has been drawn to exploring mechanisms like organelle dysfunction, primarily mitochondria and mitochondrial genome influence, while delineating the newer exploratory targets such as GBA1, GLP, LRRK2, and miRNAs and therapeutic agents targeting them. Show more

Keywords: Autophagy, mitochondrial dysfunction, mitogenome, neuroinflammation, Parkinson’s disease, oxidative stress

DOI: 10.3233/JAD-220682

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S399-S428, 2023

Authors: Wong, Genper Chi-Ngai | Chow, Kim Hei-Man

Article Type: Review Article

Abstract: Chronological aging is by far the strongest risk factor for age-related dementia and Alzheimer’s disease. Senescent cells accumulated in the aging and Alzheimer’s disease brains are now recognized as the keys to describing such an association. Cellular senescence is a classic phenomenon characterized by stable cell arrest, which is thought to be applicable only to dividing cells. Emerging evidence indicates that fully differentiated post-mitotic neurons are also capable of becoming senescent, with roles in contributing to both brain aging and disease pathogenesis. The key question that arises is the identity of the upstream triggers and the molecular mechanisms that underly …such changes. Here, we highlight the potential role of persistent DNA damage response as the major driver of senescent phenotypes and discuss the current evidence and molecular mechanisms that connect DNA repair infidelity, cell cycle re-entry and terminal fate decision in committing neuronal cell senescence. Show more

Keywords: Alzheimer’s disease, brain aging, cell cycle re-entry, neuronal cell senescence, persistent DNA damage response

DOI: 10.3233/JAD-220203

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S429-S451, 2023

Authors: Chhimpa, Neeraj | Singh, Neha | Puri, Nikkita | Kayath, Hanuman Prasad

Article Type: Review Article

Abstract: Citrate synthase is a key mitochondrial enzyme that utilizes acetyl-CoA and oxaloacetate to form citrate in the mitochondrial membrane, which participates in energy production in the TCA cycle and linked to the electron transport chain. Citrate transports through a citrate malate pump and synthesizes acetyl-CoA and acetylcholine (ACh) in neuronal cytoplasm. In a mature brain, acetyl-CoA is mainly utilized for ACh synthesis and is responsible for memory and cognition. Studies have shown low citrate synthase in different regions of brain in Alzheimer’s disease (AD) patients, which reduces mitochondrial citrate, cellular bioenergetics, neurocytoplasmic citrate, acetyl-CoA, and ACh synthesis. Reduced citrate mediated …low energy favors amyloid-β (Aβ) aggregation. Citrate inhibits Aβ25–35 and Aβ1–40 aggregation in vitro . Hence, citrate can be a better therapeutic option for AD by improving cellular energy and ACh synthesis, and inhibiting Aβ aggregation, which prevents tau hyperphosphorylation and glycogen synthase kinase-3 beta. Therefore, we need clinical studies if citrate reverses Aβ deposition by balancing mitochondrial energy pathway and neurocytoplasmic ACh production. Furthermore, in AD’s silent phase pathophysiology, when neuronal cells are highly active, they shift ATP utilization from oxidative phosphorylation to glycolysis and prevent excessive generation of hydrogen peroxide and reactive oxygen species (oxidative stress) as neuroprotective action, which upregulates glucose transporter-3 (GLUT3) and pyruvate dehydrogenase kinase-3 (PDK3). PDK3 inhibits pyruvate dehydrogenase, which decreases mitochondrial-acetyl-CoA, citrate, and cellular bioenergetics, and decreases neurocytoplasmic citrate, acetyl-CoA, and ACh formation, thus initiating AD pathophysiology. Therefore, GLUT3 and PDK3 can be biomarkers for silent phase of AD. Show more

Keywords: Acetyl-CoA, acetylcholine, Alzheimer’s disease, amyloid-beta, APOE ɛ4, cellular bioenergetics, citrate, citrate synthase, GLUT3

DOI: 10.3233/JAD-220514

Citation: Journal of Alzheimer's Disease, vol. 94, no. s1, pp. S453-S472, 2023