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

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