Research Paper Volume 12, Issue 16 pp 15995—16020

Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer’s disease: a pre-clinical study

Valentina Cecarini1, , Laura Bonfili1, , Olee Gogoi1, , Solomon Lawrence1, , Franco M. Venanzi2, , Vasco Azevedo3, , Pamela Mancha-Agresti3,4, , Mariana Martins Drumond3,4,5, , Giacomo Rossi1, , Sara Berardi1, , Livio Galosi1, , Massimiliano Cuccioloni1, , Mauro Angeletti1, , Jan S. Suchodolski6, , Rachel Pilla6, , Jonathan A. Lidbury6, , Anna Maria Eleuteri1, ,

  • 1 School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, Camerino, Italy
  • 2 CureLab Oncology, Inc., Dedham, Boston, MA 02026, USA
  • 3 Laboratório de Genética Celular e Molecular, Instituto de Ciências Biológicas, Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
  • 4 FAMINAS- BH, Belo Horizonte, Minas Gerais, Brazil
  • 5 Centro Federal de Educação Tecnológica de Minas Gerais (CEFET/MG), Departamento de Ciências Biológicas, Belo Horizonte, Brazil
  • 6 Gastrointestinal Laboratory, Department of Small Animal Clinical Science, Texas A&M University, College Station, TX 77843, USA

Received: April 10, 2020       Accepted: July 14, 2020       Published: August 28, 2020
How to Cite

Copyright © 2020 Cecarini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Alzheimer’s disease (AD) is a progressive neurodegeneration characterized by neuron death ending in memory and cognitive decline. A major concern in AD research is the identification of new therapeutics that could prevent or delay the onset of the disorder, with current treatments being effective only in reducing symptoms. In this perspective, the use of engineered probiotics as therapeutic tools for the delivery of molecules to eukaryotic cells is finding application in several disorders. This work introduces a new strategy for AD treatment based on the use of a Lactobacillus lactis 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.


AD: Alzheimer’s disease; h-p62: human p62; m-p62: murine p62; LAB: lactobacilli added with the pExu:empty plasmid; p62-LAB: lactobacilli added with the pExu vector encoding for the human p62 protein; Aβ(1–40): amyloid-beta peptide (1-40); Aβ(1–42): amyloid-beta peptide (1-42); AMC: 7-amino-4-methylcoumarin; AFC: 7-amido-4-trifluoro-methylcoumarin; pAB: 4-aminobenzoic acid; AP-N: aminopeptidase-N; BrAAP: branched-chain amino acid preferring; ChT-L: chymotrypsin-like; T-L: trypsin-like; PGPH: peptidylglutamyl-peptide hydrolyzing; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; Cat B: cathepsin B; Cat L: cathepsin L; 4-HNE: 4-hydroxy-2-nonenal; 3-NT: 3-nitrotyrosine; 8-oxodG: 8-oxo-7:8-dihydro-2′-deoxyguanosine; OGG1: 8-oxoguanine DNA glycosylase-1; GIP: glucose-dependent insulinotropic polypeptide; GLP-1: glucagon like peptide-1; TNF-α: tumor necrosis factor-α; INF-γ: interferon-γ.