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1.
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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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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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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Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer's Disease: A Narrative Review.
Puga, AM, Ruperto, M, Samaniego-Vaesken, ML, Montero-Bravo, A, Partearroyo, T, Varela-Moreiras, G
Nutrients. 2021;(9)
Abstract
Cognitive impairment and Alzheimer's Disease, among other cognitive dysfunctions, has been recognized as a major public health problem. Folic acid is a well-known essential nutrient whose deficiency has been linked to neurocognitive dysfunctions, owing to hyperhomocysteinemia, an independent risk factor for cardio- and cerebrovascular diseases, including cognitive impairment, Alzheimer's Disease, and vascular dementia. However, to date, there is certain controversy about the efficacy of vitamin supplementation in patients with these pathologies. Therefore, we have reviewed the available dietary intervention studies based on folic acid, either alone or in combination with different vitamins or nutrients into the progression of Alzheimer's Disease and Cognitive impairment, highlighting the cognition and biochemical markers employed for the evaluation of the disease progression. Undeniably, the compiled information supports the potential benefits of vitamin supplementation in these pathologies, especially relevant to the aging process and quality of life, although more research is urgently needed to confirm these positive findings.
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Neuroprotective Herbs for the Management of Alzheimer's Disease.
Gregory, J, Vengalasetti, YV, Bredesen, DE, Rao, RV
Biomolecules. 2021;(4)
Abstract
Background-Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disease that is characterized by memory loss, personality changes, and a decline in cognitive function. While the exact cause of AD is still unclear, recent studies point to lifestyle, diet, environmental, and genetic factors as contributors to disease progression. The pharmaceutical approaches developed to date do not alter disease progression. More than two hundred promising drug candidates have failed clinical trials in the past decade, suggesting that the disease and its causes may be highly complex. Medicinal plants and herbal remedies are now gaining more interest as complementary and alternative interventions and are a valuable source for developing drug candidates for AD. Indeed, several scientific studies have described the use of various medicinal plants and their principal phytochemicals for the treatment of AD. This article reviews a subset of herbs for their anti-inflammatory, antioxidant, and cognitive-enhancing effects. Methods-This article systematically reviews recent studies that have investigated the role of neuroprotective herbs and their bioactive compounds for dementia associated with Alzheimer's disease and pre-Alzheimer's disease. PubMed Central, Scopus, and Google Scholar databases of articles were collected, and abstracts were reviewed for relevance to the subject matter. Conclusions-Medicinal plants have great potential as part of an overall program in the prevention and treatment of cognitive decline associated with AD. It is hoped that these medicinal plants can be used in drug discovery programs for identifying safe and efficacious small molecules for AD.
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Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease.
Marucci, G, Buccioni, M, Ben, DD, Lambertucci, C, Volpini, R, Amenta, F
Neuropharmacology. 2021;:108352
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Abstract
Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine. The ChE-Is currently available in the market are donepezil, rivastigmine and galantamine as tacrine is no longer in use, due to its hepatotoxicity. According to mechanism of action the ChE-Is are classified as short-acting or reversible agents such as tacrine, donepezil, and galantamine, as intermediate-acting or pseudo-irreversible agent such as rivastigmine. Overall, the efficacy of the three ChE-Is available in the market is similar and the benefit of administration of these compounds is mild and may not be clinically significant. Due to gastrointestinal side effects of these drugs, medicinal chemistry and pharmaceutical delivery studies have investigated solutions to improve the pharmacological activity of these compounds. In spite of the limited activity of ChE-Is, waiting for more effective approaches, these drugs still represent a pharmacotherapeutic resource for the treatment of AD. Other approaches in which ChE-Is were investigated is in their use in combination with other classes of drugs such as cholinergic precursors, N-methyl-d-aspartate (NMDA) receptor antagonists and antioxidant agents. After many years from the introduction in therapy of ChE-Is, the combination with other classes of drugs may represent the chance for a renewed interest of ChE-Is in the treatment of adult-onset dementia disorders.
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Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing.
Reiten, OK, Wilvang, MA, Mitchell, SJ, Hu, Z, Fang, EF
Mechanisms of ageing and development. 2021;:111567
Abstract
NAD+ is a fundamental molecule in human life and health as it participates in energy metabolism, cell signalling, mitochondrial homeostasis, and in dictating cell survival or death. Emerging evidence from preclinical and human studies indicates an age-dependent reduction of cellular NAD+, possibly due to reduced synthesis and increased consumption. In preclinical models, NAD+ repletion extends healthspan and / or lifespan and mitigates several conditions, such as premature ageing diseases and neurodegenerative diseases. These findings suggest that NAD+ replenishment through NAD+ precursors has great potential as a therapeutic target for ageing and age-predisposed diseases, such as Alzheimer's disease. Here, we provide an updated review on the biological activity, safety, and possible side effects of NAD+ precursors in preclinical and clinical studies. Major NAD+ precursors focused on by this review are nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and the new discovered dihydronicotinamide riboside (NRH). In summary, NAD+ precursors have an exciting therapeutic potential for ageing, metabolic and neurodegenerative diseases.
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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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The role of Bcl-2 proteins in modulating neuronal Ca2+ signaling in health and in Alzheimer's disease.
Callens, M, Kraskovskaya, N, Derevtsova, K, Annaert, W, Bultynck, G, Bezprozvanny, I, Vervliet, T
Biochimica et biophysica acta. Molecular cell research. 2021;(6):118997
Abstract
The family of B-cell lymphoma-2 (Bcl-2) proteins exerts key functions in cellular health. Bcl-2 primarily acts in mitochondria where it controls the initiation of apoptosis. However, during the last decades, it has become clear that this family of proteins is also involved in controlling intracellular Ca2+ signaling, a critical process for the function of most cell types, including neurons. Several anti- and pro-apoptotic Bcl-2 family members are expressed in neurons and impact neuronal function. Importantly, expression levels of neuronal Bcl-2 proteins are affected by age. In this review, we focus on the emerging roles of Bcl-2 proteins in neuronal cells. Specifically, we discuss how their dysregulation contributes to the onset, development, and progression of neurodegeneration in the context of Alzheimer's disease (AD). Aberrant Ca2+ signaling plays an important role in the pathogenesis of AD, and we propose that dysregulation of the Bcl-2-Ca2+ signaling axis may contribute to the progression of AD and that herein, Bcl-2 may constitute a potential therapeutic target for the treatment of AD.
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Mitochondria-associated membranes (MAMs): a potential therapeutic target for treating Alzheimer's disease.
Yu, W, Jin, H, Huang, Y
Clinical science (London, England : 1979). 2021;(1):109-126
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Abstract
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a leading global health concern for individuals and society. However, the potential mechanisms underlying the pathogenesis of AD have not yet been elucidated. Currently, the most widely acknowledged hypothesis is amyloid cascade owing to the brain characteristics of AD patients, including great quantities of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Nevertheless, the amyloid cascade hypothesis cannot address certain pathologies that precede Aβ deposition and NFTs formation in AD, such as aberrant calcium homeostasis, abnormal lipid metabolism, mitochondrial dysfunction and autophagy. Notably, these earlier pathologies are closely associated with mitochondria-associated membranes (MAMs), the physical structures connecting the endoplasmic reticulum (ER) and mitochondria, which mediate the communication between these two organelles. It is plausible that MAMs might be involved in a critical step in the cascade of earlier events, ultimately inducing neurodegeneration in AD. In this review, we focus on the role of MAMs in the regulation of AD pathologies and the potential molecular mechanisms related to MAM-mediated pathological changes in AD. An enhanced recognition of the preclinical pathogenesis in AD could provide new therapeutic strategies, shifting the modality from treatment to prevention.