Abstract
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.
Highlights
Alzheimer’s disease (AD) is an age-related progressive neurodegenerative condition and the most common cause of dementia
This study aims to explore the neuroprotective effects of the L. lactis MG1363 strain harboring the newly constructed pExu plasmid containing a eukaryotic expression cassette designed to express the human SQSTM1/p62. p62 is a multifunctional protein of 440 amino acids, which contains several structural domains that give it scaffolding ability [15]
The novel object recognition (NOR) test was performed on the four groups of mice to evaluate the effects of the treatment on hippocampal functions and recognition memory
Summary
Alzheimer’s disease (AD) is an age-related progressive neurodegenerative condition and the most common cause of dementia. AD is characterized by neuronal cell loss associated with memory and cognitive decline. It mainly affects the hippocampus, the entorhinal and the cerebral cortex. Extracellular aggregates of insoluble amyloid-β (Aβ) protein [1, 2], intracellular neurofibrillary tangles of the microtubule-associated www.aging-us.com protein tau [3], deficit in neurotransmitters and mitochondrial dysfunctions are characteristic markers of this pathology. Other harmful factors common to all neurodegenerative conditions act as major contributors to AD, among these, the decreased functionality of proteolytic systems, inflammatory processes with increased release of pro-inflammatory cytokines and oxidative damage to cellular macromolecules. Research efforts are directed towards the discovery of new disease-modifying therapies, which can block the progression of the disease and affect multiple molecular pathways [4]
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