Advancing Alzheimer's Disease research through a preclinical model of SERPINA3

Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia, with no available cure or disease-modifying therapy. Pathologically, AD is characterized by amyloid beta (Aβ) deposition, neuronal loss, synaptic dysfunction, and glial cell-mediated neuroinflammation. Among inflammatory mediators, SERPINA3, a serine protease inhibitor, has been implicated in AD pathogenesis. SERPINA3 is a major component of amyloid plaques, and its overexpression in glial cells exacerbates AD-like pathology in transgenic mouse models. However, its precise role in disease progression remains poorly understood. To investigate the role of SERPINA3 in AD, we generated a Serpina3-deficient mouse model (Serpina3LD/LD). While the human genome encodes a single SERPINA3 gene, the mouse genome contains a cluster of 14 orthologs. Our model was engineered to delete all 14 Serpina3 genes, enabling a more accurate assessment of SERPINA3 function in disease. Crossing Serpina3 LD/LD mice with the 5XFAD amyloidogenic model resulted in a striking 50 - 60% reduction in plaque burden within the brain of these animals, highlighting SERPINA3 as a key mediator of AD pathogenesis and a promising therapeutic target. While ongoing studies aiming to elucidate the mechanisms underlying this phenotype are under way, here we seek to accelerate translational research by developing and validating a humanized SERPINA3 mouse model in the context of AD. This model will facilitate in vivo testing of SERPINA3-targeted therapeutics, advancing the development of novel treatments for AD. Project Number: 1R21AG098408-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Stephane Pelletier | Institution: INDIANA UNIVERSITY INDIANAPOLIS, INDIANAPOLIS, IN | Award Amount: $435,875 | Activity Code: R21 | Study Section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11287272