ADAM10 as a biomarker for Alzheimer's disease: A systematic review.

BACKGROUND: Studies have shown that A Disintegrin and Metalloproteinase 10 (ADAM10) is the main α-secretase in the non-amyloidogenic cleavage of the amyloid precursor protein (APP), avoiding the production of amyloid-ß peptide (Aß), one of the pathological hallmarks of Alzheimer's disease (AD). OBJECTIVE: To investigate ADAM10 from cerebrospinal fluid (CSF) and plasma/serum as a potential biomarker for AD. METHODS: A systematic review was carried out in the MEDLINE/PubMed, Web of Science, Embase, and Scopus databases using the terms and Boolean operators: "Alzheimer" AND "ADAM10" AND "biomarker". Citation searching was also adopted. The inclusion criteria were original studies of ADAM10 in blood or CSF in patients with AD. The risk of bias was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The analysis methods were registered in the PROSPERO database (#CRD42021274239). RESULTS: Of the 97 records screened, 17 were included. There is strong evidence for lower levels of ADAM10 in platelets of persons with AD compared to cognitively healthy participants. On the other hand, higher levels of ADAM10 were found in plasma. Regarding CSF, controversial results were found with lower and higher levels of ADAM10 in persons with AD compared to healthy older adults. The differences may be due to diverse reasons, including different sample collection and processing and different antibodies, highlighting the importance of standardizing the experiments and choosing the appropriate antibodies for ADAM10 detection. CONCLUSION: Evidence shows that ADAM10 levels are altered in platelets, plasma, serum, and CSF of individuals with AD. The alteration was evident in all stages of the disease, and therefore, the protein may represent a complementary biomarker for the disease. However, more studies must be performed to establish cut-off values for ADAM10 levels to discriminate AD participants from cognitively unimpaired older adults.

Historic concepts of dementia and Alzheimer's disease: From ancient times to the present.

The aim of this work is to describe the history of dementia and Alzheimer's disease (AD) concepts, from early descriptions in antiquity, through studies and authors from different historical periods throughout the centuries, to the latest updates of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). The article also presents the inclusion of the biomarkers from the cerebrospinal fluid, such as Tau and phosphorylated Tau proteins and beta-amyloid peptide in the most recent diagnostic criteria. A literature search was carried out in order to construct a reflexive narrative review of studies dated up to 2015 in the LILACS and Medline databases and with the inclusion of bibliographical references of the area. The different terms used throughout the history of the dementia and Alzheimer's disease concepts were contextualized according to the scientific perspective of a given epoch and its way of producing and reproducing knowledge. The concepts of dementia and AD continue to evolve, largely due to their complexity. Considering the importance and the growth of AD cases in the last and the next decades, this review may contribute in practice with the historical knowledge of the concepts related to dementia and AD.

Sarcopenia, frailty and their prevention by exercise.

Sarcopenia is a major component of the frailty syndrome, both being considered as strong predictors of morbidity, disability, and death in older people. In this review, we explore the definitions of sarcopenia and frailty and summarize the current knowledge on their relationship with oxidative stress and the possible therapeutic interventions to prevent or treat them, including exercise-based interventions and multimodal strategies. We highlight the relevance of the impairment of the nervous system and of the anabolic response (protein synthesis) in muscle aging leading to frailty and sarcopenia. We also discuss the importance of malnutrition and physical inactivity in these geriatric syndromes. Finally, we propose multimodal interventions, including exercise programs and nutritional supplementation, as the strategies to prevent and treat both sarcopenia and frailty.

Translation, Adaptation and Validation of Rapid Geriatric Assessment to the Brazilian context.

OBJECTIVES: Translate, cross-culturally adapt and validate the Rapid Geriatric Assessment (RGA) for Brazilian community-dwelling adults. DESIGN: Cross-sectional study, using a quantitative approach. SETTING: Urban population from the city of São Carlos, located in the interior of São Paulo State, Brazil. PARTICIPANTS: 148 individuals aged 60 or over. MEASUREMENTS: Participants were assessed using the RGA, Fried Frailty Phenotype, International Physical Activity Questionnaire - long version, Addenbrooke´s Cognitive Exam - Revised Version, Mini Nutritional Assessment, short Form - 36, EuroQol 5-Dimension, Geriatric Depression Scale - short version, in addition to performing Dual Energy X-ray Absorptiometry to diagnose sarcopenia, according to the criteria established by the European Working Group on Sarcopenia in Older People. RESULTS: In the translation and adaption process of the RGA, steps recommended by the literature were followed: initial translation, synthesis of translations, backward translation, evaluation from the panel of judges, and pre-test. When evaluating the psychometric properties of the scale, satisfactory reliability (internal consistency and stability) and validity (content, concurrent criterion and convergent, divergent and discriminant construct) were verified. CONCLUSION: The Brazilian version of the RGA is reliable and valid, and can be used in the Brazilian context to evaluate the elderly population.

Identifying Frailty Levels and Associated Factors in a Population Living in the Context of Poverty and Social Vulnerability.

This study aimed to investigate a vulnerable population living in the context of poverty in a Brazilian municipality, in order to identify the factors that are associated with frailty syndrome in elderly people. From the total population living in the area, a random sample of 363 community-dwelling people, 60 years and older, age and gender-stratified, was selected to participate in the research. After losses, a sample of 304 older adults was classified as non-frail, pre-frail and frail. According to the Fried frailty criteria, the prevalence was 12.2% for non-frail individuals, 60.5% pre-frail and 27.3% frail. The main factors associated with frailty in the studied sample were low level of physical activity (OR: 5.2, 95%CI: 2.5-11.0), the occurrence of two or more falls within 12 months (OR: 3.1, 95%CI: 1.4-7.1), mobility deficits (OR: 3.0, 95%CI: 1.5-5.8), and depressive symptoms (OR: 1.9, 95%CI: 1.1-3.7). This study identified the most important factors that must be evaluated to identify frailty syndrome in a socially vulnerable population in the context of poverty. The data should help to encourage effective strategies concerning public health policies for this population.

Alternagin-C, a disintegrin-like protein from the venom of Bothrops alternatus, modulates alpha2ß1 integrin-mediated cell adhesion, migration and proliferation

The alpha2ß1 integrin is a major collagen receptor that plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Alternagin-C (ALT-C), a disintegrin-like protein purified from the venom of the Brazilian snake Bothrops alternatus, competitively interacts with the alpha2ß1 integrin, thereby inhibiting collagen binding. When immobilized in plate wells, ALT-C supports the adhesion of fibroblasts as well as of human vein endothelial cells (HUVEC) and does not detach cells previously bound to collagen I. ALT-C is a strong inducer of HUVEC proliferation in vitro. Gene expression analysis was done using an Affimetrix HU-95A probe array with probe sets of 10,000 human genes. In human fibroblasts growing on collagen-coated plates, ALT-C up-regulates the expression of several growth factors including vascular endothelial growth factor, as well as some cell cycle control genes. Up-regulation of the vascular endothelial growth factor gene and other growth factors could explain the positive effect on HUVEC proliferation. ALT-C also strongly activates protein kinase B phosphorylation, a signaling event involved in endothelial cell survival and angiogenesis. In human neutrophils, ALT-C has a potent chemotactic effect modulated by the intracellular signaling cascade characteristic of integrin-activated pathways. Thus, ALT-C acts as a survival factor, promoting adhesion, migration and endothelial cell proliferation after binding to alpha2ß1 integrin on the cell surface. The biological activities of ALT-C may be helpful as a therapeutic strategy in tissue regeneration as well as in the design of new therapeutic agents targeting alpha2ß1 integrin.

Alternagin-C, a disintegrin-like protein from the venom of Bothrops alternatus, modulates alpha2beta1 integrin-mediated cell adhesion, migration and proliferation.

The alpha2beta1 integrin is a major collagen receptor that plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Alternagin-C (ALT-C), a disintegrin-like protein purified from the venom of the Brazilian snake Bothrops alternatus, competitively interacts with the alpha2beta1 integrin, thereby inhibiting collagen binding. When immobilized in plate wells, ALT-C supports the adhesion of fibroblasts as well as of human vein endothelial cells (HUVEC) and does not detach cells previously bound to collagen I. ALT-C is a strong inducer of HUVEC proliferation in vitro. Gene expression analysis was done using an Affimetrix HU-95A probe array with probe sets of approximately 10,000 human genes. In human fibroblasts growing on collagen-coated plates, ALT-C up-regulates the expression of several growth factors including vascular endothelial growth factor, as well as some cell cycle control genes. Up-regulation of the vascular endothelial growth factor gene and other growth factors could explain the positive effect on HUVEC proliferation. ALT-C also strongly activates protein kinase B phosphorylation, a signaling event involved in endothelial cell survival and angiogenesis. In human neutrophils, ALT-C has a potent chemotactic effect modulated by the intracellular signaling cascade characteristic of integrin-activated pathways. Thus, ALT-C acts as a survival factor, promoting adhesion, migration and endothelial cell proliferation after binding to alpha2beta1 integrin on the cell surface. The biological activities of ALT-C may be helpful as a therapeutic strategy in tissue regeneration as well as in the design of new therapeutic agents targeting alpha2beta1 integrin.

BaG, a new dimeric metalloproteinase/disintegrin from the Bothrops alternatus snake venom that interacts with alpha5beta1 integrin.

The alpha(5)beta(1) integrin is one of the major fibronectin receptors which plays an essential role in the adhesion of normal and tumor cells to extracellular matrix. Here, we describe the isolation and characterization of a novel dimeric metalloproteinase/disintegrin, which is an inhibitor of fibronectin binding to the alpha(5)beta(1) integrin. This protein (BaG) was isolated from the venom of the South American snake Bothrops alternatus by gelatin-Sepharose affinity and anion exchange chromatography. The molecular mass of BaG was approximately 130 kDa under non-reducing conditions and 55 kDa under reducing conditions by SDS-PAGE. BaG shows proteolytic activity on casein that was inhibited by EDTA. 1,10-phenanthroline-treated BaG (BaG-I) inhibits ADP-induced platelet aggregation with an IC(50) of 190 nM. BaG-I inhibits fibronectin-mediated K562 cell adhesion with an IC(50) of 3.75 microM. K562 cells bind to BaG-I probably through interaction with alpha(5)beta(1) integrin, since anti-alpha(5)beta(1) antibodies inhibited K562 cell adhesion to BaG-I. In addition, BaG-I induces the detachment of K562 cells that were bound to fibronectin. In summary, we have purified a novel, dimeric snake venom metalloproteinase/disintegrin that binds to the alpha(5)beta(1) integrin.