ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review.

Background: Blood-based biomarkers can be very useful in formulating new diagnostic and treatment proposals in the field of dementia, especially in Alzheimer’s disease (AD). However, due to the influence of several factors on the reproducibility and reliability of these markers, their clinical use is still very uncertain. Thus, up-to-date knowledge about the main blood biomarkers that are currently being studied is extremely important in order to discover clinically useful and applicable tools, which could also be used as novel pharmacological strategies for the AD treatment. Objective: The aim of this paper was to carry out a literature review on the major blood-based biomarkers for AD, connecting them with the pathophysiology of the disease. Methods: A narrative review was performed based on the current candidates of blood-based biomarkers for AD to show the main results from different studies, focusing on their clinical applicability and association with AD pathogenesis. Results: Recent advances in the search of blood-based AD biomarkers were summarized in this review. The biomarkers were classified according to the topics related to the main hallmarks of the disease such as inflammation, amyloid, and tau deposition, synaptic degeneration and oxidative stress. Moreover, molecules involved in the regulation of proteins related to these hallmarks were described, such as non-coding RNAs, neurotrophins, growth factors and metabolites. Cells or cellular components with the potential to be considered as blood-based AD biomarkers were described in a separate topic. Conclusion: A series of limitations undermine new discoveries on blood-based AD biomarkers. The lack of reproducibility of findings due to the small size and heterogeneity of the study population, different analytical methods and other assay conditions make longitudinal studies necessary in this field to validate these structures, especially when considering a clinical evaluation that includes a broad panel of these potential and promising blood-based biomarkers.

ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity as a protease. In this study, we investigated ADAM10 activity in plasma and CSF samples of patients with amnestic mild cognitive impairment (aMCI) and mild AD compared with cognitively healthy controls. Our results indicated that plasma levels of soluble ADAM10 were significantly increased in the mild AD group, and that in these samples the protease was inactive, as determined by activity assays. The same results were observed in CSF samples, indicating that the increased plasma ADAM10 levels reflect the levels found in the central nervous system. In SH-SY5Y neuroblastoma cells, ADAM10 achieves its major protease activity in the fraction obtained from plasma membrane lysis, where the mature form of the enzyme is detected, confirming the importance of ADAM10 localization for its activity. Taken together, our results demonstrate the potential of plasma ADAM10 to act as a biomarker for AD, highlighting its advantages as a less invasive, easier, faster, and lower-cost processing procedure, compared to existing biomarkers.

Background Nonspecific neck pain is a multifactorial and very common condition in adult individuals, traditional acupuncture (TA) and laser acupuncture (LA) may be treatment options for certain individuals in such a condition. However, no reports were found in the literature comparing the effectiveness of TA and LA in cases of chronic nonspecific neck pain. Therefore, the aim of the present study is to investigate the effectiveness of TA and LA therapies in individuals with chronic nonspecific neck pain, noting which one is more efficient for this condition. The result of this research will have direct implications for pain management and, consequently, may benefit individuals suffering from nonspecific chronic neck pain. Methods/design This will be a controlled and randomized clinical trial. Eighty-four individuals will be recruited and distributed equally and randomly into 3 groups: TA (which will receive the acupuncture treatment with needles), LA (which will receive the laser acupuncture treatment), and Sham (who will receive the placebo intervention). The acupuncture points (Tianzhu, Fengchi, Jianjing, and Jianzhongshu) will be stimulated bilaterally. The primary outcome will be pain intensity, determined using the Numerical Rating Scale. The secondary outcomes will be pressure pain threshold, temporal summation of pain, conditioned pain modulation, use of analgesic medicines after treatment, and the global perceived effect scale. The assessments will be performed immediately before and after the treatment, which will be a single session, at the follow-up and 1 month after the end of the treatments; evaluation will be made of the pain intensity and the global perceived effect. Statistical analysis of the data obtained will consider a significance level of p < 0.05. Discussion This study will provide evidence concerning the effects of LA treatment, in comparison with TA and sham intervention, leading to benefits for individuals suffering from chronic nonspecific neck pain. Trial registration Brazilian Registry of Clinical Trials - ReBEC RBR-7vbw5gd. Date of registration: August 06th, 2021.

Biomarkers capable of identifying and distinguishing types of dementia such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) have been become increasingly relentless. Studies of possible biomarker proteins in the blood that can help formulate new diagnostic proposals and therapeutic visions of different types of dementia are needed. However, due to several limitations of these biomarkers, especially in discerning dementia, their clinical applications are still undetermined. Thus, the updating of biomarker blood proteins that can help in the diagnosis and discrimination of these main dementia conditions is essential to enable new pharmacological and clinical management strategies, with specificities for each type of dementia. To review the literature concerning protein blood-based AD and non-AD biomarkers as new pharmacological targets and/or therapeutic strategies. Recent findings for protein-based AD, PDD, LBD, and FTD biomarkers are focused on in this review. Protein biomarkers were classified according to the pathophysiology of the dementia types. The diagnosis and distinction of dementia through protein biomarkers is still a challenge. The lack of exclusive biomarkers for each type of dementia highlights the need for further studies in this field. Only after this, blood biomarkers may have a valid use in clinical practice as they are promising to help in diagnosis and in the differentiation of diseases.