Evaluation of the Anti-Amyloid Potential of Parawixin 10: An Acylpolyamine Isolated from the Venom of the Spider Parawixia bistriata in the Context of Alzheimer's Disease

• Grant number: 24/23138-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2025
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Zoology - Applied Zoology
• Principal Investigator: Wagner Ferreira dos Santos
• Grantee: Beatriz Perez Piccolo
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Spider venoms represent a rich biochemical arsenal of bioactive molecules, the result of millions of years of evolution. Among these, low-molecular-weight compounds such as acylpolyamines are particularly important. The spider *Parawixia bistriata* displays a unique behavioral ecology, living in social groups during its reproductive phase. Previous findings from our laboratory have demonstrated that several isolated venom fractions exhibit anticonvulsant and neuroprotective activities. In earlier projects (FAPESP grants nº 14/21419-2, nº 2022/07638-0, and nº 2023/11938-1), we identified antimicrobial and, notably, anti-amyloid activities in both crude venom and purified fractions, using in vitro assays with aSA53T and AB proteins, which are implicated in Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. We now highlight Parawixin10 (Pwx10), a compound with anticonvulsant properties that also confers neuroprotection in glutamate-induced excitotoxicity models. Pwx10 enhances the activity of glutamate transporters EAAT1 and EAAT2. Given that the AD pathogenic cascade involves L-glutamate-mediated excitotoxicity and loss of EAAT2 function, our goal is to investigate the potential of Pwx10 as a therapeutic agent against AD. Pwx10 will be isolated using LC-MS/MS and evaluated in vitro for its ability to modulate A¿ aggregation using thioflavin-based assays. We will also perform cell viability tests and employ the triple-transgenic mouse model for Alzheimer's disease (3xTg-AD), which will be subjected to behavioral testing using the Elevated Plus Maze and the Novel Object Recognition task. Additionally, we will assess the neuroprotective effects of Pwx10 through immunohistochemistry and immunofluorescence, as well as quantify A¿ oligomers via ELISA. Our study is innovative and pioneering in the search for neuroactive compounds derived from spider venoms targeting neurodegenerative diseases. Most importantly, it underscores the urgent need to explore and preserve our biodiversity as a valuable source of natural compounds for translational biology, before anthropogenic actions compromise these rich biological resources.