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Dietary Nutrients and Prevention of Alzheimer's Disease.
Chauhan, PS, Yadav, D, Arukha, AP
CNS & neurological disorders drug targets. 2022;(3):217-227
Abstract
Alzheimer's disease is an irrevocable, progressive brain disorder that gradually destroys memory and cognitive skills. One of the extensively studied methods of preventing Alzheimer's disease (AD) progression is by providing a nutritional diet. Several reports have shown that intake of nutritional elements as huperzine A, ursolic acid, vitamins etc., can directly influence pathogenesis of AD. Surprisingly, the occurrence of metabolic disorders due to an unhealthy diet has been known to be a major environmental cause of AD. It has been noted that AD severity can be controlled by supplementing dietary supplements containing huge amounts of health-promoting ingredients. These elements promote cell health, regeneration, and the anti-aging process that specifically interrupt the pathogenic pathways in AD development. Fortunately, incorporating changes in the nutritional content is inexpensive, easy, acceptable, safe, effective, and in most cases, free from major adverse events. Many nutritional phytoconstituents such as flavonoids, alkaloids, and terpenoids are still being evaluated in the hope of identifying a successful therapy for AD. This review discusses the therapeutical potential of several key nutrients that have been researched for treating AD treatment and the method of their neuroprotective intervention.
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Trace concentrations, heavy implications: Influences of biometals on major brain pathologies of Alzheimer's disease.
Lippi, SLP, Neely, CLC, Amaya, AL
The international journal of biochemistry & cell biology. 2022;:106136
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition that involves accumulation of toxic protein species, notably amyloid-β (Aβ)plaques and neurofibrillary tau tangles that are associated with cognitive decline. These proteins can bind metal ions, ultimately affecting their structure and function. In this review, we discuss key biometals such as zinc, copper, and iron that interact with protein species involved in AD, mainly Aβ, tau, and the late-onset AD risk factor Apolipoprotein E (APOE). These metals interact with Aβ and tau proteins, affecting their aggregation and toxicity. The allele variants of APOE also have different interactions with these metals, affecting APOE protein expression and aggregation of AD protein species.
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Direct Modulation of the Gut Microbiota as a Therapeutic Approach for Alzheimer's Disease.
Wang, Y, Dykes, GA
CNS & neurological disorders drug targets. 2022;(1):14-25
Abstract
Alzheimer's disease is a neurodegenerative disease characterized by a progressive decline in memory and cognitive functions. It is a multifactorial disease involving a wide range of pathological factors that are not fully understood. As supported by a growing amount of evidence in recent years, gut microbiota plays an important role in the pathogenesis of Alzheimer's disease through the brain-gut-microbiota axis. This suggests that direct modulation of the gut microbiota can be a potential therapeutic target for Alzheimer's disease. This review summarizes recent research findings on the modulation of the gut microbiota by probiotic therapies and faecal microbiota transplantation for controlling the pathologies of Alzheimer's disease. Current limitations and future research directions of this field are also discussed.
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Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group.
Dubois, B, Villain, N, Frisoni, GB, Rabinovici, GD, Sabbagh, M, Cappa, S, Bejanin, A, Bombois, S, Epelbaum, S, Teichmann, M, et al
The Lancet. Neurology. 2021;(6):484-496
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Abstract
In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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Promotion and Inhibition of Amyloid-β Peptide Aggregation: Molecular Dynamics Studies.
Itoh, SG, Okumura, H
International journal of molecular sciences. 2021;(4)
Abstract
Aggregates of amyloid-β (Aβ) peptides are known to be related to Alzheimer's disease. Their aggregation is enhanced at hydrophilic-hydrophobic interfaces, such as a cell membrane surface and air-water interface, and is inhibited by polyphenols, such as myricetin and rosmarinic acid. We review molecular dynamics (MD) simulation approaches of a full-length Aβ peptide, Aβ40, and Aβ(16-22) fragments in these environments. Since these peptides have both hydrophilic and hydrophobic amino acid residues, they tend to exist at the interfaces. The high concentration of the peptides accelerates the aggregation there. In addition, Aβ40 forms a β-hairpin structure, and this structure accelerates the aggregation. We also describe the inhibition mechanism of the Aβ(16-22) aggregation by polyphenols. The aggregation of Aβ(16-22) fragments is caused mainly by the electrostatic attraction between charged amino acid residues known as Lys16 and Glu22. Since polyphenols form hydrogen bonds between their hydroxy and carboxyl groups and these charged amino acid residues, they inhibit the aggregation.
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Nutrition-Based Approaches in Clinical Trials Targeting Cognitive Function: Highlights of the CTAD 2020.
Giudici, KV
The journal of prevention of Alzheimer's disease. 2021;(2):118-122
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Abstract
The Clinical Trials on Alzheimer's Disease (CTAD) 2020 conference was the stage for researchers from all over the world to present their recent and ongoing research focused on potential Alzheimer's disease (AD) treatments and prevention of cognitive decline. Among a varied range of topics, nutritional aspects arose as possibilities of treatments towards the promotion of a healthy aging. Among the discussed themes, supplementation of omega-3 polyunsaturated fatty acids and multi-nutrient approaches were presented, suggesting that long-term supplementation (i.e., over 3 years) might be needed for observing positive effects on cognitive performance. Trials testing ketogenic agents and carbohydrate-restricted diet were also presented and showed promising effects on improving cognitive function of mild-cognitive impaired (MCI) and pre-diabetic individuals, respectively, in a short-term way (i.e. after 3 to 6 months). The combination of some of the nutritional approaches with physical activity interventions raises the question on whether they would individually perform in a similar way. Promising therapies involving nutrition appear to be safe and well tolerated by volunteers. Failures on achieving positive findings raise questions on whether they were driven by specific characteristics of the studied populations, insufficient doses or duration of treatment. Notwithstanding, current evidence on the applicability of nutrition-based approaches as AD treatments are encouraging but demand further research on the topic.
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Glutathione: An Old and Small Molecule with Great Functions and New Applications in the Brain and in Alzheimer's Disease.
Haddad, M, Hervé, V, Ben Khedher, MR, Rabanel, JM, Ramassamy, C
Antioxidants & redox signaling. 2021;(4):270-292
Abstract
Significance: Glutathione (GSH) represents the most abundant and the main antioxidant in the body with important functions in the brain related to Alzheimer's disease (AD). Recent Advances: Oxidative stress is one of the central mechanisms in AD. We and others have demonstrated the alteration of GSH levels in the AD brain, its important role in the detoxification of advanced glycation end-products and of acrolein, a by-product of lipid peroxidation. Recent in vivo studies found a decrease of GSH in several areas of the brain from control, mild cognitive impairment, and AD subjects, which are correlated with cognitive decline. Critical Issues: Several strategies were developed to restore its intracellular level with the l-cysteine prodrugs or the oral administration of γ-glutamylcysteine to prevent alterations observed in AD. To date, no benefit on GSH level or on oxidative biomarkers has been reported in clinical trials. Thus, it remains uncertain if GSH could be considered a potential preventive or therapeutic approach or a biomarker for AD. Future Directions: We address how GSH-coupled nanocarriers represent a promising approach for the functionalization of nanocarriers to overcome the blood/brain barrier (BBB) for the brain delivery of GSH while avoiding cellular toxicity. It is also important to address the presence of GSH in exosomes for its potential intercellular transfer or its shuttle across the BBB under certain conditions. Antioxid. Redox Signal. 35, 270-292.
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A Primer on the Evolution of Aducanumab: The First Antibody Approved for Treatment of Alzheimer's Disease.
Mukhopadhyay, S, Banerjee, D
Journal of Alzheimer's disease : JAD. 2021;(4):1537-1552
Abstract
Alzheimer's disease (AD) is the most common form of dementia with global burden projected to triple by 2050. It incurs significant biopsychosocial burden worldwide with limited treatment options. Aducanumab is the first monoclonal antibody recently approved by the US-FDA for mild AD through the accelerated approval pathway. It is the first molecule to be approved for AD since 2003 and carries with it a therapeutic promise for the future. As the definition of AD has evolved from a pathological entity to a Clinico-biological construct over the years, the amyloid-β (Aβ) pathway has been increasingly implicated in its pathogenesis. The approval of Aducanumab is based on reduction of the Aβ load in the brain, which forms a surrogate marker for this pathway. The research populace has, however, been globally divided by skepticism and hope regarding this approval. Failure to meet clinical endpoints in the trials, alleged transparency issues, cost-effectiveness, potential adverse effects, need for regular monitoring, and critique of 'amyloid cascade hypothesis' itself are the main caveats concerning the antibody. With this controversy in background, this paper critically looks at antibody research in AD therapeutics, evidence, and evolution of Aducanumab as a drug and the potential clinical implications of its use in future. While the efficacy of this monoclonal antibody in AD stands as a test of time, based on the growing evidence it is vital to rethink and explore alternate pathways of pathogenesis (oxidative stress, neuroinflammation, cholesterol metabolism, vascular factors, etc.) as possible therapeutic targets that may help elucidate the enigma of this complex yet progressive and debilitating neurodegenerative disorder.
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Bile Acids as Key Modulators of the Brain-Gut-Microbiota Axis in Alzheimer's Disease.
Mulak, A
Journal of Alzheimer's disease : JAD. 2021;(2):461-477
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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.
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A Review of Oxidative Stress Products and Related Genes in Early Alzheimer's Disease.
Cioffi, F, Adam, RHI, Bansal, R, Broersen, K
Journal of Alzheimer's disease : JAD. 2021;(3):977-1001
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Abstract
Oxidative stress is associated with the progression of Alzheimer's disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type 1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients.