Inactive plasmatic ADAM10 levels in subjects with mild cognitive impairment and Alzheimer's Disease

• Grant number: 18/05446-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): August 01, 2018
• Effective date (End): September 30, 2020
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Márcia Regina Cominetti
• Grantee: Marina Mantellatto Grigoli
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil

Abstract

In dementias, changes in brain functioning and progressive and global loss of cognitive functions are observed, interfering with the individual's social and occupational activities, with dementia of Alzheimer's disease (AD) being the main one. Biomarkers that can diagnose AD in its early stages, preferably in samples that do not require highly invasive collection procedures, are the target of many studies recently and present a great clinical challenge. DA is strongly related to the formation, accumulation and aggregation of ²-amyloid peptide (²A) in neurons. This molecule is formed by the sequential cleavage of ² and ³-secretases, via an amyloidogenic pathway. In contrast, sequential cleavage by ± and ³-secretase, through the non-amyloidogenic pathway, prevents the formation of neuronal ²A, and consequently, the onset and progression of AD. ADAM10 is the main neuronal ±-secretase and is also present in platelets, white cells and cerebrospinal fluid. Studies of our and other groups indicate that ADAM10 levels in platelets of patients with AD are decreased compared to cognitively healthy subjects. Thus, ADAM10 is a strong candidate for AD blood biomarker AD. ADAM10 is a type I membrane protein and only when anchored to it, has activity. In this sense, this study intends to evaluate the levels and activity of ADAM10 in the blood plasma of subjects with AD dementia and mild cognitive impairment (MCI). Previous results from our group allow us to elaborate the hypothesis of this study that the levels of soluble and therefore inactive plasma ADAM10 in patients with MCI and AD would be increased compared to the levels of cognitively healthy subjects. Detection of inactive ADAM10 in plasma would allow a diagnostic advance for AD, since there would be no need for platelet collection and separation. In addition, this study may reinforce the knowledge of the biological activity of ADAM10, which could bring great advances in the area. In dementias, changes in brain functioning and progressive and global loss of cognitive functions are observed, interfering with the individual's social and occupational activities, with dementia of Alzheimer's disease (AD) being the main one. Biomarkers that can diagnose AD in its early stages, preferably in samples that do not require highly invasive collection procedures, are the target of many studies recently and present a great clinical challenge. DA is strongly related to the formation, accumulation and aggregation of ²-amyloid peptide (²A) in neurons. This molecule is formed by the sequential cleavage of ² and ³-secretases, via an amyloidogenic pathway. In contrast, sequential cleavage by ± and ³-secretase, through the non-amyloidogenic pathway, prevents the formation of neuronal ²A, and consequently, the onset and progression of AD. ADAM10 is the main neuronal ±-secretase and is also present in platelets, white cells and cerebrospinal fluid. Studies of our and other groups indicate that ADAM10 levels in platelets of patients with AD are decreased compared to cognitively healthy subjects. Thus, ADAM10 is a strong candidate for AD blood biomarker AD. ADAM10 is a type I membrane protein and only when anchored to it, has activity. In this sense, this study intends to evaluate the levels and activity of ADAM10 in the blood plasma of subjects with AD dementia and mild cognitive impairment (MCI). Previous results from our group allow us to elaborate the hypothesis of this study that the levels of soluble and therefore inactive plasma ADAM10 in patients with MCI and AD would be increased compared to the levels of cognitively healthy subjects. Detection of inactive ADAM10 in plasma would allow a diagnostic advance for AD, since there would be no need for platelet collection and separation. In addition, this study may reinforce the knowledge of the biological activity of ADAM10, which could bring great advances in the area. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MANZINE, PATRICIA R.; VATANABE, IZABELA P.; PERON, RAFAELA; GRIGOLI, MARINA M.; PEDROSO, V, RENATA; NASCIMENTO, CARLA M. C.; COMINETTI, MARCIA R.. Blood-based Biomarkers of Alzheimer's Disease: The Long and Winding Road. CURRENT PHARMACEUTICAL DESIGN, v. 26, n. 12, p. 1300-1315, 2020. (16/06226-9, 15/26084-1, 19/02648-4, 17/18808-5, 18/05446-0)

MANZINE, PATRICIA R.; VATANABE, IZABELA P.; GRIGOLI, MARINA M.; PEDROSO, RENATA, V; MONTEIRO, MARIA PATRICIA A. O.; OLIVEIRA, DANIELLE S. M. S.; NASCIMENTO, CARLA M. C.; PERON, RAFAELA; ORLANDI, FABIANA S.; COMINETTI, MARCIA R.. Potential Protein Blood-based Biomarkers in Different Types of Dementia: A Therapeutic Overview. CURRENT PHARMACEUTICAL DESIGN, v. 28, n. 14, p. 17-pg., 2022-01-01. (19/26709-2, 19/26444-9, 14/21066-2, 21/01906-0, 16/06226-9, 19/02648-4, 17/18808-5, 20/12915-7, 18/05446-0)