Non-coding RNAs in Regulation of Protein Aggregation and Clearance Pathways: Current Perspectives Towards Alzheimer's Research and Therapy.

Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 45.0 million people worldwide and ranking as the fifth leading cause of mortality. AD is identified by neurofibrillary tangles (NFTs), which include abnormally phosphorylated tau-protein and amyloid protein (amyloid plaques). Peptide dysregulation is caused by an imbalance between the production and clearance of the amyloid-beta (Aß) and NFT. AD begins to develop when these peptides are not cleared from the body. As a result, understanding the processes that control both normal and pathological protein recycling in neuronal cells is critical. Insufficient Aß and NFT clearance are important factors in the development of AD. Autophagy, lysosomal dysfunction, and ubiquitin-proteasome dysfunction have potential roles in the pathogenesis of many neurodegenerative disorders, particularly in AD. Modulation of these pathways may provide a novel treatment strategy for AD. Non-coding RNAs (ncRNAs) have recently emerged as important biological regulators, with particular relevance to the emergence and development of neurodegenerative disorders such as AD. ncRNAs can be used as potential therapeutic targets and diagnostic biomarkers due to their critical regulatory functions in several biological processes involved in disease development, such as the aggregation and accumulation of Aß and NFT. It is evident that ncRNAs play a role in the pathophysiology of AD. In this communication, we explored the link between ncRNAs and AD and their regulatory mechanisms that may help in finding new therapeutic targets and AD medications.

Discovery of novel harmine derivatives as GSK-3ß/DYRK1A dual inhibitors for Alzheimer's disease treatment.

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.

Pathophysiological mechanism and natural preventive and therapeutic strategies of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the presence of two types of protein deposits in the brain, amyloid plaques and neurofibrillary tangles. The first one are dense deposits of beta amyloid protein, the second one are dense deposits of the protein tau. These proteins are present in all of our brains, but in AD they act unusually, leading to neuronal degeneration. This review will provide an overview of the AD, including the role of amyloid beta and tau, and mechanisms that lead to the formation of plaques and tangles. The review will also cover the existing researches that have focused on the inhibition of amyloid beta formation, cholinesterase, tau hyperphosphorylation, the pathogenic mechanisms of apoE4, and GSK-3 as a solution that could be used to slow or prevent the disease.

Tau-aggregation inhibition: promising role of nanoencapsulated dietary molecules in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a cumulative form of dementia associated with memory loss, cognition impairment, and finally leading to death. AD is characterized by abnormal deposits of extracellular beta-amyloid and intracellular Tau-protein tangles throughout the brain. During pathological conditions of AD, Tau protein undergoes various modifications and aggregates over time. A number of clinical trials on patients with AD symptoms have indicated the effectiveness of Tau-based therapies over anti-Aß treatments. Thus, there is a huge paradigm shift toward Tau aggregation inhibitors. Several bioactives of plants and microbes have been suggested to cross the neuronal cell membrane and play a crucial role in managing neurodegenerative disorders. Bioactives mainly act as active modulators of AD pathology besides having antioxidant and anti-inflammatory potential. Studies also demonstrated the potential role of dietary molecules in inhibiting the formation of Tau aggregates and removing toxic Tau. Further, these molecules in nonencapsulated form exert enhanced Tau aggregation inhibition activity both in in vitro and in vivo studies suggesting a remarkable role of nanoencapsulation in AD management. The present article aims to review and discuss the structure-function relationship of Tau protein, the post-translational modifications that aid Tau aggregation and potential bioactives that inhibit Tau aggregation.

Natural Products with BACE1 and GSK3ß Inhibitory Activity.

Alzheimer's disease (AD) is a neurodegenerative, progressive, and fatal disorder characterized by marked atrophy of the cerebral cortex and loss of basal forebrain cholinergic neurons. The main pathological features of AD are related to neuronal degeneration and include extracellular deposition of amyloid beta plaques (Aß plaques), intracellular formation of neurofibrillary tangles (NFTs), and neuroinflammation. So far, drugs used to treat AD have symptomatic and palliative pharmacological effects, disappearing with continued use due to neuron degeneration and death. Therefore, there are still problems with an effective drug for treating AD. Few approaches evaluate the action of natural products other than alkaloids on the molecular targets of ß-amyloid protein (Aß protein) and/or tau protein, which are important targets for developing neuroprotective drugs that will effectively contribute to finding a prophylactic drug for AD. This review gathers and categorizes classes of natural products, excluding alkaloids, which in silico analysis (molecular docking) and in vitro and/or in vivo assays can inhibit the BACE1 and GSK-3ß enzymes involved in AD.

The inhibitory effect of Curcumin-Artemisinin co-amorphous on Tau aggregation and Tau phosphorylation.

Tau is a natively unfolded microtubule-associated protein. Tau neurofibrillary tangles are one of the hallmarks of Alzheimer's disease. The post-translational modifications of Tau lead to its pathological state. Phosphorylation is the key post-translational modification associated with Tauopathy. Curcumin is a polyphenolic compound present in the rhizomes of Curcuma longa. Curcumin has been reported to have remarkable medicinal properties in several diseases, but its poor solubility limits its therapeutic potency. Artemisinin is a sesquiterpene lactone, which has been known sience ancient times for its applications as a treatment for various diseases such as malaria, cancer, autoimmune disease, etc. In the present study, the potency of crystalline curcumin, crystalline artemisinin, and Cur-Art co-amorphous dispersion were evaluated against Tau pathology. The in-vitro ThS/ANS fluorescence and electron microscopy results suggested that curcumin and Cur-Art efficiently inhibited Tau aggregation. Furthermore, exposure to curcumin and Cur-Art co-amorphous restored the impaired nuclear transport in formaldehyde-stressed cells. Curcumin was also found to modulate the phosphorylation of Tau, which indicated the neuroprotective potency. Thus, curcumin and Cur-Art co-amorphous exhibit therapeutic potential against Tau protein in Alzheimer's disease.

Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico.

Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aß, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aß, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.

Glimepiride mitigates tauopathy and neuroinflammation in P301S transgenic mice: role of AKT/GSK3ß signaling.

BACKGROUND AND OBJECTIVE: Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study. METHODS: P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests. RESULTS: GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3ß, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels. CONCLUSION: The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy.

GSK-3ß and its Inhibitors in Alzheimer's Disease: A Recent Update.

Alzheimer's disease (AD) is an emerging major health and socioeconomic burden worldwide. It is characterized by neuronal loss, memory loss and cognitive impairment in the aging population. Despite several scientific advancements over the past five decades, the underlying molecular mechanism of the disease progression is yet unknown. Glycogen synthase kinase-3ß (GSK-3ß) has huge implications on the brain function, causing molecular pathologies, neuronal damage and impairment of brain performance in AD. It is one of the key players in signaling pathways for normal brain functioning and a critical molecular link between amyloid-beta (Aß) and tau neurofibrillary tangles (NFTs). GSK-3ß activation is driven by phosphorylation of tau(τ) protein which results in disruption of neuronal synaptic activities and the formation of neuronal plaques. Although the accumulation of Aß plaques and intracellular tangles of hyperphosphorylated tau protein has been well established as neuropathological hallmarks of the disease, the molecular mechanism has not been unraveled. This review focuses on the role of GSK-3ß in the molecular mechanisms participating in the manifestation and progression of AD. The review also suggests that GSK-3ß inhibitors can be used as potential therapeutic targets for amelioration of AD.

Blood pressure, antihypertensive drugs, and incident frailty: The Multidomain Alzheimer Preventive Trial (MAPT).

OBJECTIVES: To examine the association of (1) high and low blood pressure (BP) and (2) antihypertensive (AH) drug use with incident frailty. STUDY DESIGN: We conducted a secondary analysis of data from the Multidomain Alzheimer Preventive Trial (MAPT), in which 1394 non-frail community-dwelling participants aged ≥70 years were followed up for 5 years. BP was measured once at baseline in a lying position using a validated electronic device. High BP was defined as systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg, and low BP as systolic BP ≤ 110 mm Hg and/or diastolic BP ≤ 70 mm Hg. AH drugs were assessed at baseline and classified according to the Anatomical Therapeutic Chemical (ATC) code. MAIN OUTCOME MEASURES: Incident frailty over the 5 years was assessed using the Fried phenotype. Cox proportional hazards models were used for the analyses. RESULTS: Low BP was associated with a greater risk of frailty (HR = 1.43, 95% CI [1.07-1.92], p = 0.02) after adjustment for age, sex, education, AH drug use, BMI, diabetes, ischemic heart disease, congestive heart failure, AF, stroke, MAPT randomization group, sit-to-stand chair test and pre-frailty. Participants with low BP and those on two or more AH drugs were at the greatest risk of frailty. Neither high BP (HR = 0.84, 95% CI [0.63-1.22], p = 0.24) nor AH drug use (HR = 1.21, 95% CI [0.89-1.64], p = 0.22) was independently associated with incident frailty. CONCLUSIONS: Low BP could be used as a new marker for identifying older adults at higher risk of frailty. CLINICALTRIALS: gov registration number: NCT00672685.

Drug delivery of memantine with carbon dots for Alzheimer's disease: blood-brain barrier penetration and inhibition of tau aggregation.

Neurofibrillary tangle, composed of aggregated tau protein, is a pathological hallmark of Alzheimer's disease (AD). The inhibition of tau aggregation is therefore an important direction for AD drug discovery. In this work, we explored the efficacy of two types of carbon dots in targeting tau aggregation, as versatile nano-carriers for the development of carbon dots (CDs)-based AD therapy. We carried out synthesis, biophysical and biochemical characterizations of two types of CDs, namely, carbon nitride dots (CNDs) and black carbon dots (B-CDs). CDs, which are biocompatible and non-toxic, were successfully conjugated with memantine hydrochloride (MH) through EDC/NHS mediated amidation reactions followed by systematic characterizations using various biophysical techniques including UV-vis spectroscopy (UV-vis), photoluminescence (PL), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), mass spectrometry (MS), Transmission electron microscopy (TEM) and atomic force microscopy (AFM). The surface diversity along with small particle sizes of CDs allowed facile delivery of MH across the blood-brain barrier (BBB), as demonstrated using a zebrafish in vivo model. The tau aggregation inhibition experiments were conducted using the thioflavin-T (ThT) assay to identify the most effective inhibitor. The kinetics and magnitude of tau aggregation were measured in the presence of CDs, which demonstrates that both B-CDs-MH and B-CDs alone are the most effective inhibitors of tau aggregation with IC50 values of 1.5 ± 0.3 and 1.6 ± 1.5 µg/mL, respectively. Taken together, our findings hold therapeutic significance to enhance the efficient delivery of MH to target AD pathology in the brain for improved efficacy.

"Drug-Carrier" Synergy Therapy for Amyloid-ß Clearance and Inhibition of Tau Phosphorylation via Biomimetic Lipid Nanocomposite Assembly.

Amyloid-ß (Aß) toxicity is considered to be companioned by Tau phosphorylation in Alzheimer's disease (AD). The clinical AD therapy is usually subjected to low blood-brain barrier (BBB) penetration and complex interaction mechanisms between Aß and phosphorylated Tau. A "Drug-Carrier" synergy therapy is herein designed to simultaneously target Aß and Tau-associated pathways for AD treatment. To imitate natural nanoparticle configuration, the endogenous apolipoprotein A-I and its mimicking peptide 4F fused angiopep-2 (Ang) are sequentially grafted onto lipid nanocomposite (APLN), providing liberty of BBB crossing and microglia targeted Aß clearance. For synergy treatment, methylene blue (MB) is further assembled into APLN (APLN/MB) for Tau aggregation inhibition. After intravenous administration, the optimized density (5 wt%) of Ang ligands dramatically enhances APLN/MB intracerebral shuttling and accumulation, which is 2.15-fold higher than that Ang absent-modification. The site-specific release of MB collaborates APLN to promote Aß capture for microglia endocytosis clearance and reduce p-Tau level by 25.31% in AD pathogenesis. In AD-Aß-Tau bearing mouse models, APLN/MB can relieve AD symptoms, rescue neuron viability and cognitive functions. Collectively, it is confirmed that "Drug-Carrier" synergy therapy of APLN/MB is a promising approach in the development of AD treatments.

Recent Advancements in Strategies for Abnormal Protein Clearance in Alzheimer's Disease.

Alzheimer's disease (AD) is an intricate neurodegenerative disease with chronic and progressive development whose typical neuropathological features encompass senile plaques and neurofibrillary tangles, respectively formed by the extracellular deposition of amyloid-beta (Aß) and the intracellular accumulation of hyperphosphorylated tau protein in the brain, particularly in limbic and cortical regions. The pathological changes are considered to be caused by the loss of Aß and tau protein clearance mechanisms under pathological conditions, which leads to an imbalance between the rates of clearance and production. Consequently, the main strategies for treating AD aim to reduce the production of Aß and hyperphosphorylated tau protein in the brain, inhibit their accumulation, or accelerate their clearance. Although drugs utilizing these therapeutic strategies have been studied successively, their therapeutic effects have generally been less than ideal. Fortunately, recent advances have been made in clearance strategies for these abnormally expressed proteins, including immunotherapies and nanomedicines targeting Aß or tau, which could represent an important breakthrough for treating AD. Here, we review recent development of the strategies for the removal of abnormal proteins and provide new ideas and methods for treating AD.

Alzheimer's Disease and other Tauopathies: Exploring Efficacy of Medicinal Plant-derived Compounds in Alleviating Tau-mediated Neurodegeneration.

Alzheimer's disease (AD), a major form of dementia, has been reported to affect more than 50 million people worldwide. It is characterized by the presence of amyloid-ß (Aß) plaques and hyperphosphorylated Tau-associated neurofibrillary tangles in the brain. Apart from AD, microtubule (MT)-associated protein Tau is also involved in other neurodegenerative diseases called tauopathies, including Pick's disease, frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration. The recent unsuccessful phase III clinical trials related to Aß- targeted therapeutic drugs have indicated that alternative targets, such as Tau, should be studied to discover more effective and safer drugs. Recent drug discovery approaches to reduce AD-related Tau pathologies are primarily based on blocking Tau aggregation, inhibiting Tau phosphorylation, compensating impaired Tau function with MT-stabilizing agents, and targeting the degradation pathways in neuronal cells to degrade Tau protein aggregates. Owing to several limitations of the currently available Tau-directed drugs, further studies are required to generate further effective and safer Tau-based disease-modifying drugs. Here, we review the studies focused on medicinal plant- derived compounds capable of modulating the Tau protein, which is significantly elevated and hyperphosphorylated in AD and other tauopathies. We have mainly considered the studies focused on Tau protein as a therapeutic target. We have reviewed several pertinent papers retrieved from PubMed and ScienceDirect using relevant keywords, with a primary focus on the Tau-targeting compounds from medicinal plants. These compounds include indolines, phenolics, flavonoids, coumarins, alkaloids, and iridoids, which have been scientifically proven to be Tau-targeting candidates for the treatment of AD.

Recent Progress Towards Vaccines and Antibody-based Therapies Against Alzheimer's Disease.

Alzheimer's disease (AD), one of the progressive neurodegenerative disorders, is characterized by clinical features such as memory loss, acquired skill loss, apraxia, and interpersonal and social communication disorders. The AD hallmarks at the neuropathological level include intracellular neurofibrillary tangles constituted by the hyperphosphorylated tau protein as well as the senile extracellular plaques dominated by the amyloid-ß (Aß) deposits. At present, AD treatment that mainly targeted towards improving symptoms and effective drugs to delay or stop disease progression is lacking. Vaccines and antibody-based therapies are a type of natural, synthetic, and gene recombinant biological product that treat or prevent disease progression by stimulating specific or non-specific immune responses. Compared with traditional targeted drugs, vaccines and antibodybased therapies have better safety and effectiveness and can even maintain the expression and stability of Aß and Tau proteins in patients for a long time. Logically, vaccines and antibody-based therapies are somewhat different from traditional drugs because these drugs can achieve the therapeutic effect of AD by activating immune cells and regulating the immune system of patients themselves, thereby clearing disease-related proteins and long-term survival. Complete cure is also observed in some patients after receiving the immunotherapy. Currently available vaccines and antibody-based therapies mainly target Aß and phosphorylated tau proteins. There are 44 vaccines and antibodybased therapies for AD, among which nine drugs are discontinued, three drugs are inactive, eleven drugs are in clinical phase 1, twelve drugs are in clinical phase 2, and seven drugs are in clinical phase 3. Currently, no vaccines and antibody-based therapies have been approved for AD treatment. In this paper, we review and analyse the research progress of vaccines and antibody-based therapies that are used to treat AD.

Intelligently thermoresponsive flower-like hollow nano-ruthenium system for sustained release of nerve growth factor to inhibit hyperphosphorylation of tau and neuronal damage for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) seriously affects human health and life and lacks effective treatments. The lessons of many clinical trial failures suggest that targeting amyloid beta to treat AD is difficult, and finding new targets is an important direction for AD drug research. The neurofibrillary tangles formed by hyperphosphorylation of tau protein induce the production of cytotoxic reactive oxygen species (ROS) and cause neuronal apoptosis. Therefore, inhibition of hyperphosphorylation of tau protein and reduction of neuronal damage have become promising methods for the treatment of AD. We herein designed a novel nanocomposite with high stability and good biocompatibility by using flower-shaped hollow nano-ruthenium (Ru NPs) as a carrier, loading nerve growth factor (NGF) and sealing with phase change material (PCM). Due to its excellent photothermal effect, under the near-infrared (NIR) irradiation, the nanocomposite could effectively penetrate the blood-brain barrier (BBB) and respond to phase changes in the lesion area, releasing NGF, which inhibited tau hyperphosphorylation, reduced oxidative stress, and more importantly restored nerve damage and maintained neuronal morphology, thereby significantly improving learning and memory in AD mice. Thus, the experimental results indicate that multifunctional nanocomposites may be a promising drug in the treatment of AD.

Anti-Alzheimer's Materials Isolated from Marine Bio-resources: A Review.

The most common type of dementia found in the elderly population is Alzheimer's disease. The disease not only impacts the patients and their families but also the society therefore, the main focus of researchers is to search new bioactive materials for treating AD. The marine environment is a rich source of functional ingredients and to date, we can find sufficient research relating to anti- Alzheimer's compounds isolated from marine environment. Therefore, this review focuses on the anti- Alzheimer's material from marine bio-resources and then expounds on the anti-Alzheimer's compounds from marine seaweed, marine animal and marine microorganisms. Moreover, because of the complexity of the disease, different hypothesizes have been elaborated and active compounds have been isolated to inhibit different stages of pathophysiological mechanisms. Sulfated polysaccharides, glycoprotein, and enzymatic hydrolysates from marine seaweeds, peptides, dietary omega-3 polyunsaturated fatty acids and skeletal polysaccharide from marine animals and secondary metabolites from marine microorganism are summarized in this review under the anti-Alzheimer's compounds from the marine.

Tau immunotherapy for Alzheimer's disease.

Targeting pathological tau protein in Alzheimer's disease (AD) and related tauopathies has shown great potential in animal models. Given that tau lesions correlate better with the degree of dementia than do amyloid-ß (Aß) plaques, their clearance may be clinically more efficacious than removing Aß when cognitive deficits become evident in AD. Several complementary mechanisms of antibody-mediated removal of tau aggregates are likely to act in concert and the importance of each one may depend on antibody properties, the disease, and its stage. Clinical trials of tau immunotherapy are already underway and several more are likely to be initiated in the near future.

Mechanisms of action of therapeutic amyloidogenic hexapeptides in amelioration of inflammatory brain disease.

Amyloid fibrils composed of peptides as short as six amino acids are effective therapeutics for experimental autoimmune encephalomyelitis (EAE). Immunosuppression arises from at least two pathways: (1) expression of type 1 IFN by pDCs, which were induced by neutrophil extracellular traps arising from the endocytosis of the fibrils; and (2) the reduced expression of IFN-γ, TNF, and IL-6. The two independent pathways stimulated by the fibrils can act in concert to be immunosuppressive in Th1 indications, or in opposition, resulting in inflammation when Th17 T lymphocytes are predominant. The generation of type 1 IFN can be minimized by using polar, nonionizable, amyloidogenic peptides, which are effective in both Th1 and Th17 polarized EAE.

Efeito da ingestão de taurina no desempenho físico: uma revisão sistemática / Effect of taurine intake on physical performance: a systematic review

Objetivo. Presentar los efectos de la taurina (Tau) en la capacidad aeróbica y anaeróbica, además de describir sus mecanismos de acción. Método. Se ha realizado una revisión sistemática de la literatura en las bases de datos PubMed/Medline y SportDiscus, teniendo como criterios de inclusión estudios con humanos, publicados en lengua inglesa, entre el 1 de enero de 2000 hasta el 1 de septiembre de 2011. La manera de consumo de Tau fue: Tau aislada o como ingrediente de bebidas energéticas evaluada con un suplemento placebo. La calidad de los estudios seleccionados fue valorada por la escala de PEDro siendo considerados los artículos con puntuaciones por encima de 5. Resultados. Fueron seleccionados 14 estudios, siendo 11 los que obtuvieron cambios en la capacidad física aeróbica y 3 en la anaeróbica. Se observaron mejoras significativas en las actividades aeróbicas (8 de los 11 artículos) de igual manera que en las anaeróbicas (2 de los 3 estudios) tras ingesta de Tau frente a placebo. Conclusión. El consumo agudo de apenas 1 g de Tau, independiente del tiempo previo de ingesta presentó un efecto positivo frente la capacidad física aeróbica y anaeróbica. El principal efecto ergogénico que se observó en el componente aerobio fue aumentar la capacidad temporal para realizar un ejercicio, sin embargo en la actividad anaerobia proporcionó una mejora en la respuesta de los iones de calcio durante la contracción muscular(AU)

Objective. Describe the effects of taurine (Tau) on aerobic and anaerobic physical performance as well as its mechanisms of action. Method. A systematic literature review on PubMed/Medline and SPORTDiscus was performed, including studies on humans which were published in English between January 1st, 2000 and September 1st, 2011.The forms of Tau intake were as the isolated compound (Tau) or as an ingredient in energy drinks analyzed with a placebo supplement. The quality of the selected articles was assessed using the PEDro scale and included articles with at least 5 points. Results. After the filtering process, 14 studies were selected from which 11 presented changes in aerobic physical performance and 3 in anaerobic physical performance. Significant improvements were observed in aerobic activities (8 out of 11 articles) and in anaerobic activities (2 out of 3 studies) after intake of Tau, compared to the placebo. Conclusion. The consumption of only 1 g of Tau, regardless of the time prior to intake, showed a beneficial effect on aerobic and anaerobic physical performance. The main ergogenic effect observed in the aerobic component was an increase on the temporal capacity of performing an exercise, whereas for the anaerobic activity there was a better response of calcium ions during muscle contraction(AU)