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Evaluation of NLRP1 and NLRP3 inflammasome pathways in Alzheimer's disease: a clinicopathological study

Grant number: 20/14339-3
Support Opportunities:Regular Research Grants
Duration: July 01, 2021 - September 30, 2023
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Claudia Kimie Suemoto
Grantee:Claudia Kimie Suemoto
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated researchers:Antonio Lucio Teixeira Junior ; lea tenenholz grinberg

Abstract

Alzheimer's disease (AD) is the main cause of dementia worldwide. The definitive diagnosis of DA is clinicopathological and based on amyloid ² (A²) plaques and neurofibrillary tangles. However, the link between amyloid cascade and depositions of phosphorylated tau (p-tau) is still missing. In this scenario, neuroinflammation appears to play an important role. Experimental models of AD have been suggesting that A² accumulation induces, through microglia, activation of the NLRP3 inflammasome, which contributes to the dissemination of A² and p-tau. Also, in experimental model, NLPR1 promoted neuronal pyroptosis. In AD, there are no neuropathological characterization of the NLRP1 and NLRP3 inflammasomes pathway in the human brain. The aim of the current project is to analyze the immunostaining profile and quantify the expression of aforementioned pathway's proteins in hippocampi of patients with AD, compared to subjects without DA. We also seek to investigate the association between neuroinflammation, neuronal pyroptosis, and severity of dementia in patients. We will use hippocampi from the Brain Bank of the Biobank for Aging Studies. The proteins NLRP3, NLRP1, ASC, caspase-1, IL-1², IL-18 and cleaved gasdermin D will be identified in hippocampal samples using immunohistochemistry. The slides will be scanned and the percentage of immunostained cells will be calculated in the hippocampal subfields. The astroglial and microglial expression of NLRP1 and NLPR3 will be evaluated, as well as the colocalization of NLRP3/NLRP1 and caspase-1 using immunofluorescence. Finally, we will investigate the relationship between severity of dementia in subjects with DA, adjusting the analysis by number of A² plaques and neurofibrillary tangles. (AU)

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