S4-04-02: Phage therapy of Alzheimer's disease

Abstract

Background: Bacteriophages, viruses that infect bacteria, are the most numerous life forms on earth, and their natural contact with human beings is not incidental but rather constant and intensive. Classic phage therapy with lytic phages, as an alternative to antibiotics, was developed for clinical use by research groups in Europe and the USA. Here, we propose a new therapeutic approach for Alzheimer’s disease (AD) based on non-lytic filamentous phages. The current dominant theory of AD etiology and pathogenesis is related to the amyloid cascade hypothesis which states that overproduction of amyloid-beta-peptide (A P), or failure to clear this peptide, leads to Alzheimer’s disease primarily through amyloid deposition, presumed to be involved in neurofibrillary tangles formation. Methods: Mice were treated intranasally with filamentous phage for 12 months. During this period, cognitive tests were conducted to check mice memory and olfaction functions, followed by neuropathological investigation of treated versus untreated mice. Results: Experiments conducted in mice models of AD showed therapeutic benefits of phage treatment. We demonstrate that the linear structure of filamentous phage (a nanotubular appearance, 900 nm long and 7 nm diameter) confers permeability to the brain, improving cognitive and olfactory functions, and dissolving -amyloid plaques. Phages were eliminated from the brain and body via urine and feces. No adverse effects were shown in peripheral organs: kidneys, liver, lungs and spleen biology was normal. Conclusions: The proposed new approach, based on intranasal application of phage, presents several important advantages. It provides a rapid delivery route into the central nervous system (CNS) due to the unique connection between the nose and brain and targets the olfactory system, shown to be one of the first brain parts affected by Alzheimer’s disease. The therapeutic potential of phage stems from its lack of natural tropism for mammalian cells. Moreover, phage therapy may overcome some of the drawbacks of -amyloid immunotherapy, such as hemorrhages and inflammation, suggesting that filamentous phage may play a therapeutic role in treating AD as well as other amyloidogenic diseases. This is the first attempt to use filamentous phages as a therapeutic agent for treatment of a mouse model of Alzheimer’s disease.