Preventing cognitive decline in Alzheimer’s disease by immunotherapies targeting inflammatory fragments derived from dysbiotic microbiota.

Mariana Vinacur, BA
Department of Medicine
Division of Infectious Diseases
Poster Overview

Alzheimer’s disease (AD) is associated with accumulation of protein deposits in the brain that destroy brain cells. Recent evidence suggests that infectious agents may substantially contribute to AD. Normally microbes reside peacefully in our bodies but in individuals susceptible to AD they might gain access to the blood or other pathways resulting in their entry into the brain where they contribute to brain cell death. We propose it is likely an accumulation over time of factors from different microbes normally residing in or on our bodies contribute to AD. We have identified a factor common to these many different microbes that allow us to test whether there are infectious agents in the brain of AD individuals and if we can use a vaccine to this factor to prevent AD. Investigating brains from a mouse model of AD, as well as humans with AD, indicated the presence of this factor in affected brains, but not from those without AD. In a mouse model of AD the vaccine prevented loss of brain function as measured in behavioral and cognitive tests. Thus we have support for a role microbes in the cause of AD, as well as an approach to prevent AD cognitive.

Scientific Abstract

Alzheimer’s disease (AD), the most common cause of dementia, is associated with the accumulation and deposition of β-amyloid in plaques, vascular amyloid, and neurofibrillary tau tangles in the brain. Recent evidence suggests that infectious agents may substantially contribute to AD neuropathology. Disrupted epithelial barriers allow microbes and/or microbial fragments access to the brain. We propose it is likely that there is no one predominant microbial species driving AD inflammation, but instead an accumulation over time of factors from multiple microbial species that contribute to AD pathology result in neuropathology. We have investigated whether a conserved microbial antigen termed PNAG could be used to detect microbes or their fragments in the brain as well as serve as a vaccine target. Active immunization against PNAG starting at  5 weeks of age in the APP/PS1 mouse AD model resulted in prevention of behavioral and cognitive defects, as assessed by open field locomotion and water T maze acquisition and reversal studies conducted at 10-12 months of age. Immunohistochemical studies of mouse and human AD brains showed the presence of PNAG-expressing microbes and microbial fragments, indicative of a microbial etiology in cognitive decline, as well as an approach to prevent this decline.

Clinical Implications
Validation of these findings could provide a fairly rapid path to clinical trials with reagents already tested in humans and available for human trials to prevent cognitive decline in individuals with Alzheimer’s disease.
Research Areas
Authors
Mariana Vinacur Franklin; Casey Roberts, Barbara Calderone,Gerald Pier, and Colette Cywes Bentley
Principal Investigator
Colette Cywes Bentley

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