Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer’s disease: a pre-clinical study
Valentina Cecarini, Laura Bonfili, Olee Gogoi, Solomon Lawrence, Franco Maria Venanzi, Vasco Azevedo, Pamela Mancha-Agresti, Mariana Martins Drumond, Giacomo Rossi, Sara Berardi, Livio Galosi, Massimiliano Cuccioloni, Mauro Angeletti, Jan S. Suchodolski, Rachel Pilla, Jonathan A. Lidbury, Anna Maria Eleuteri
Abstract
strain carrying one plasmid (pExu) that contains a eukaryotic expression cassette encoding the human p62 protein. 3xTg-AD mice orally administered with these bacteria for two months showed an increased expression of endogenous p62 in the brain, with a protein delivery mechanism involving both lymphatic vessels and neural terminations, and positive effects on the major AD hallmarks. Mice showed ameliorated memory, modulation of the ubiquitin-proteasome system and autophagy, reduced levels of amyloid peptides, and diminished neuronal oxidative and inflammatory processes. Globally, we demonstrate that these extremely safe, non-pathogenic and non-invasive bacteria used as delivery vehicles for the p62 protein represent an innovative and realistic therapeutic approach in AD.