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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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2.
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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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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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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Widespread severe cerebral elevations of haptoglobin and haemopexin in sporadic Alzheimer's disease: Evidence for a pervasive microvasculopathy.
Philbert, SA, Xu, J, Unwin, RD, Dowsey, AW, Cooper, GJS
Biochemical and biophysical research communications. 2021;:89-94
Abstract
Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration but there are no available treatments with demonstrated disease-modifying actions. It is therefore relevant to study hitherto-unknown aspects of brain structure and function to seek new disease-related mechanisms that might be targeted by novel disease-modifying interventions. During hypothesis-generating proteomic investigations in a case-control study of sAD, we observed widespread elevations of haptoglobin and haemopexin in all six brain-regions studied, which together represent much of the brain. Measured perturbations were significant, with the posterior probability of upregulation generally >95% and haptoglobin doubling in expression levels on average across deep brain structures (hippocampus, entorhinal cortex and cingulate gyrus) as well as sensory and motor cortices, and cerebellum. Haptoglobin and haemopexin are often regarded as circulating proteins whose main functions are to bind, respectively, the strongly pro-inflammatory extracellular haemoglobin and haeme molecules that form following haemolysis, thereby promoting their clearance and suppressing damage they might otherwise cause, for example, acute kidney injury. To our knowledge, elevations in neither cerebral haptoglobin nor haemopexin have previously been linked to the pathogenesis of sAD. Post-mortem examination of these cases showed no signs of macroscopic cerebral haemorrhage. These findings demonstrate pervasive cerebral elevation of haptoglobin and haemopexin, consistent with low-level intracerebral leakage of haemoglobin and consequent haeme formation throughout sAD brain. They point to a widespread underlying microvasculopathy that facilitates erythrocyte leakage, thereby triggering elevated tissue-free haemoglobin and driving the measured elevations in haptoglobin and haemopexin.
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Chocolate consumption and all-cause and cause-specific mortality in a US population: a post hoc analysis of the PLCO cancer screening trial.
Zhong, GC, Hu, TY, Yang, PF, Peng, Y, Wu, JJ, Sun, WP, Cheng, L, Wang, CR
Aging. 2021;(14):18564-18585
Abstract
Few studies with mixed results have examined the association between chocolate consumption and mortality. We aimed to examine this association in a US population. A population-based cohort of 91891 participants aged 55 to 74 years was identified. Chocolate consumption was assessed via a food frequency questionnaire. Cox regression was used to estimate risk estimates. After an average follow-up of 13.5 years, 19586 all-cause deaths were documented. Compared with no regular chocolate consumption, the maximally adjusted hazard ratios of all-cause mortality were 0.89 [95% confidence interval (CI) 0.84-0.94], 0.84 (95% CI 0.79-0.90), 0.86 (95% CI 0.81-0.93), and 0.87 (95% CI 0.82-0.93) for >0-0.5 servings/week, >0.5-1 serving/week, >1-2 servings/week, and >2 servings/week, respectively (Ptrend = 0.009). A somewhat stronger inverse association was observed for mortality from cardiovascular disease and Alzheimer's disease. A nonlinear dose-response pattern was found for all-cause and cardiovascular mortality (all Pnonlinearity < 0.01), with the lowest risk observed at chocolate consumption of 0.7 servings/week and 0.6 servings/week, respectively. The favorable associations with all-cause and cardiovascular mortality were found to be more pronounced in never smokers than in current or former smokers (all Pinteraction < 0.05). In conclusion, chocolate consumption confers reduced risks of mortality from all causes, cardiovascular disease, and Alzheimer's disease in this US population.
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Effects of vitamin E supplementation on the risk and progression of AD: a systematic review and meta-analysis.
Wang, W, Li, J, Zhang, H, Wang, X, Zhang, X
Nutritional neuroscience. 2021;(1):13-22
Abstract
Objective: The association between vitamin E supplementation and Alzheimer's disease (AD) was controversial because of conflicting data in the literature. This study was designed to systematically evaluate evidence about the efficacy of vitamin E supplementation not only on the risk but also on the progression of AD. Design: Five electronic databases were searched for studies published up to June 2017. Articles reporting vitamin E supplementation and AD were included, and the random-effect model was performed for the meta-analysis about the relationship between vitamin E supplementation and AD. Results: Five cohort studies and three randomized controlled trial (RCT) studies (total n = 14,262) involving 1313 cases about vitamin E effects on the risk of AD and 244 cases about effects on progression of AD. The pooled RR for vitamin E supplemental and risk of AD was 0.81 [95% CI: 0.50-1.33, I 2 = 69.2%]. Suitable data could not be extracted to do meta-analysis as there was no unified standard of outcome measure for studies on AD progression. We carefully analyzed and evaluated the authenticity and accuracy of every single trial, while reliable evidence could not be obtained. Conclusions: From what we do, neither the synthetic data on risk of AD nor the critical review on progression of AD could provide enough evidence on our research. Thus, we cannot draw a specific conclusion on the association or correlation between Vitamin E and AD.
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The role of peripheral fatty acids as biomarkers for Alzheimer's disease and brain inflammation.
Cisbani, G, Bazinet, RP
Prostaglandins, leukotrienes, and essential fatty acids. 2021;:102205
Abstract
Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disease. A wide range of techniques have been proposed to facilitate early diagnosis of AD, including biomarkers from the cerebrospinal fluid and blood. Although phosphorylated tau and amyloid beta are amongst the most promising biomarkers of AD, other peripheral biomarkers have been identified and in this review we synthesize the current knowledge on circulating fatty acids. Fatty acids are involved in different biological process including neurotransmission and inflammation. Interestingly, some fatty acids appear to be modulated during disease progression, including long chain saturated fatty acids, and polyunsaturated fatty acids, such as docosahexaenoic acid . However, discrepant results have been reported in the literature and there is the need for further validation and method standardization. Nonetheless, our literature review suggests that fatty acid analyses could potentially provide a valuable source of data to further inform the pathology and progression of AD.
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Computational Evaluation of Interaction Between Curcumin Derivatives and Amyloid-β Monomers and Fibrils: Relevance to Alzheimer's Disease.
Orjuela, A, Lakey-Beitia, J, Mojica-Flores, R, Hegde, ML, Lans, I, Alí-Torres, J, Rao, KS
Journal of Alzheimer's disease : JAD. 2021;(s1):S321-S333
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Abstract
BACKGROUND The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-β (Aβ) fibrils due to the misfolding/aggregation of the Aβ peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aβ42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties. OBJECTIVE To computationally assess the interaction between Aβ peptide and a set of curcumin derivatives previously explored in experimental assays. METHODS The interactions of ten ligands with Aβ monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the Aβ42 peptide, both in the monomeric and fibril forms. RESULTS The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aβ42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aβ42 monomers occur in a region critical for peptide aggregation. CONCLUSION Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aβ monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.
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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.