Journal of Alzheimer's Disease - Volume 84, issue 2

Authors: Mulak, Agata

Article Type: Review Article

Abstract: Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer’s disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affect gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, …and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. An age-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists. Show more

Keywords: Alzheimer’s disease, bile acids, brain-gut-microbiota axis

DOI: 10.3233/JAD-210608

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 461-477, 2021

Authors: Kitani-Morii, Fukiko | Friedland, Robert P. | Yoshida, Hideki | Mizuno, Toshiki

Article Type: Review Article

Abstract: Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short …life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly’s gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior. Show more

Keywords: Alzheimer’s disease, cross-seeding, Drosophila melanogaster, gut-brain axis, gut microbiota, inflammation, neurodegeneration, Parkinson’s disease

DOI: 10.3233/JAD-215031

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 479-490, 2021

Authors: Lennon, Matthew J. | Rigney, Grant | Raymont, Vanessa | Sachdev, Perminder

Article Type: Review Article

Abstract: Effective, disease modifying therapies for Alzheimer’s disease (AD) remain a quandary, following a panoply of expensive failures in human clinical trials. Given the stagnation in therapeutics, alternative approaches are needed. Recent successes of genetic therapies in other neurodegenerative diseases may highlight the way forward. This scoping review explores suggested targets of genetic therapy in AD, with a focus on vector-based approaches in pre-clinical and clinical trials. Putative targets of genetic therapies tested in pre-clinical trials include amyloid pathway intermediates and enzymes modulation, tau protein downregulation, APOE4 downregulation and APOE2 upregulation, neurotrophin expression (nerve growth factor (NGF) and brain-derived …neurotrophic factor), and inflammatory cytokine alteration, among several other approaches. There have been three completed human clinical trials for genetic therapy in AD patients, all of which upregulated NGF in AD patients, showing some mixed evidence of benefit. Several impediments remain to be surpassed before genetic therapies can be successfully applied to AD, including the challenge of delivering monogenic genetic therapies for complex polygenic disorders, risks in the dominant delivery method (intracranial injection), stability of genetic therapies in vivo , poor translatability of pre-clinical AD models, and the expense of genetic therapy production. Genetic therapies represent an exciting opportunity within the world of AD therapeutics, but clinical applications likely remain a long term, rather than short term, possibility. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, gene, genetic therapy, review, tau, therapy

DOI: 10.3233/JAD-215145

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 491-504, 2021

Authors: Wang, Qixin | Dong, Xiaofang | Zhang, Ran | Zhao, Changqi

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a central neurodegenerative disease generally among the elderly; it accounts for approximately 50–75%of total cases of dementia patients and poses a serious threat to physical and mental health. Currently available treatments for AD mainly relieves its symptoms, and effective therapy is urgently needed. Deposition of amyloid-β protein in the brain is an early and invariant neuropathological feature of AD. Currently the main efforts in developing anti-AD drugs focus on anti-amyloidogenic therapeutics that prevent amyloid-β production or aggregation and decrease the occurrence of neurotoxic events. The results of an increasing number of studies suggest that natural extracts …and phytochemicals have a positive impact on brain aging. Flavonoids belong to the broad group of polyphenols and recent data indicate a favorable effect of flavonoids on brain aging. In this review, we collect relevant discoveries from 1999 to 2021, discuss 75 flavonoids that effectively influence AD pathogenesis, and summarize their functional mechanisms in detail. The data we have reviewed show that, these flavonoids belong to various subclasses, including flavone, flavanone, biflavone, etc. Our results provide a reference for further study of the effects of flavonoids on AD and the progress of anti-AD therapy. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, flavonoids, phytochemicals, structure-activity relationship

DOI: 10.3233/JAD-210735

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 505-533, 2021

Authors: Chen, Huiyi | Chen, Feng | Zhang, Miaoping | Chen, Yanting | Cui, Lili | Liang, Chunmei

Article Type: Review Article

Abstract: Autophagy is a basic physiological process maintaining cell renewal, the degradation of dysfunctional organelles, and the clearance of abnormal proteins and has recently been identified as a main mechanism underlying the onset and progression of Alzheimer’s disease (AD). The APOE ɛ4 genotype is the strongest genetic determinant of AD pathogenesis and initiates autophagic flux at different times. This review synthesizes the current knowledge about the potential pathogenic effects of ApoE4 on autophagy and describes its associations with the biological hallmarks of autophagy and AD from a novel perspective. Via a remarkable variety of widely accepted signaling pathway markers, such …as mTOR, TFEB, SIRT1, LC3, p62, LAMP1, LAMP2, CTSD, Rabs, and V-ATPase, ApoE isoforms differentially modulate autophagy initiation; membrane expansion, recruitment, and enclosure; autophagosome and lysosome fusion; and lysosomal degradation. Although the precise pathogenic mechanism varies for different genes and proteins, the dysregulation of autophagic flux is a key mechanism on which multiple pathogenic processes converge. Show more

Keywords: Alzheimer’s disease, apolipoproteins E, autophagy, neurodegenerative diseases

DOI: 10.3233/JAD-210602

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 535-555, 2021

Authors: Song, Jiayi | Yang, Xuehan | Zhang, Ming | Wang, Chunyan | Chen, Li

Article Type: Review Article

Abstract: Glutamate is the main excitatory neurotransmitter in the brain, and its excitatory neurotoxicity is closely related to the occurrence and development of Alzheimer’s disease. However, increasing evidence shows that in the process of Alzheimer’s disease, glutamate is not only limited to its excitotoxicity as a neurotransmitter but also related to the disorder of its metabolic balance. The balance of glutamate metabolism in the brain is an important determinant of central nervous system health, and the maintenance of this balance is closely related to glutamate uptake, glutamate circulation, intracellular mitochondrial transport, and mitochondrial metabolism. In this paper, we intend to elaborate …the key role of mitochondrial glutamate metabolism in the pathogenesis of Alzheimer’s disease and review glutamate metabolism in mitochondria as a potential target in the treatment of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, glutamate metabolism, glutamate synthesis, mitochondria

DOI: 10.3233/JAD-210595

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 557-578, 2021

Authors: Golzari-Sorkheh, Mahdieh | Brown, Carla E. | Weaver, Donald F. | Reed, Mark A.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia. Although AD is one of the most socioeconomically devastating diseases confronting humanity, no “curative” disease modifying drug has been identified. Recent decades have witnessed repeated failures of drug trials and have called into question the utility of the amyloid hypothesis approach to AD therapeutics design. Accordingly, new neurochemical processes are being evaluated and explored as sources of alternative druggable targets. Among these newly identified targets, neuroinflammation is emerging as a front-runner, and within the realm of neuroinflammation, the inflammasome, particularly the NLRP3 complex, is garnering focussed attention. This review summarizes …current data and approaches to understanding the role of the NLRP3 inflammasome in neuroinflammation and AD, and systematically identifies and evaluates multiple targets within the NLRP3 inflammasome cascade as putative drug targets. Show more

Keywords: Alzheimer’s disease, dementia, inflammasome, innate immune, NLRP3

DOI: 10.3233/JAD-210660

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 579-598, 2021

Authors: Nan, Haitian | Kim, Yeon-Jeong | Tsuchiya, Mai | Fukao, Toko | Hara, Noriko | Hagihara, Atsushi | Nishioka, Kenya | Hattori, Nobutaka | Hara, Norikazu | Ikeuchi, Takeshi | Ohtsuka, Toshihisa | Takiyama, Yoshihisa

Article Type: Short Communication

Abstract: Familial dementia is a rare inherited disease involving progressive impairment of memory, thinking, and behavior. We report a novel heterozygous pathogenic variant (c.199G > A, p.Val67Ile) in the CIAO1 gene that appears to be co-segregated with Alzheimer’s disease in a Japanese family. Biochemical analysis of CIAO1 protein revealed that the variant increases the interaction of CIAO1 with immature amyloid-β protein precursor (AβPP), but not mature or soluble AβPP, indicating plausible CIAO1 involvement in AβPP processing. Our study indicates that a heterozygous variant in the CIAO1 gene may be closely related to autosomal dominant familial dementia.

Keywords: Alzheimer’s disease, amyloid-β protein precursor processing, CIAO1, CIAO1 protein, cognitive decline, dementia, familial, neurogenetics

DOI: 10.3233/JAD-210706

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 599-605, 2021

Authors: Block, Michelle L. | Kodavanti, Urmila P.

Article Type: Article Commentary

Abstract: The mechanisms underlying how urban air pollution exposure conveys Alzheimer’s disease risk and affects plaque pathology is largely unknown. Because particulate matter, the particle component of urban air pollution, varies across location, pollution source, and time, a single model representative of all ambient particulate matter is unfeasible for research investigating the role of ar pollution in central nervous system diseases. More specifically, the investigation of several models of particulate matter with enrichment of source-specific components are essential to employ, in order to more fully understand what characteristics of particulate matter affects Alzheimer’s disease, including standardized diesel exhaust particles.

Keywords: Air pollution, Alzheimer’s disease, diesel exhaust particles, particulate matter models

DOI: 10.3233/JAD-215201

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 607-608, 2021

Authors: Robinson, Andrew C. | Davidson, Yvonne S. | Roncaroli, Federico | Minshull, James | Tinkler, Phillip | Cairns, Margaret | Horan, Michael A. | Payton, Antony | Mann, David M.A.

Article Type: Research Article

Abstract: Background: Early diagnosis of Alzheimer’s disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown. Objective: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, …Thal phase, and Braak stage). Methods: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants. Results: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found. Conclusion: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, ‘at risk’ individuals could be targeted for early interventions which could attenuate the progression of the disease. Show more

Keywords: Cognitive dysfunction, dementia, neuropathology, neuropsychological test

DOI: 10.3233/JAD-215102

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 609-619, 2021