Do Microbiome-Derived Cell Fragments in the Brain Accelerate Transition from TBI to AD/ADRD?
Abstract
Traumatic brain injury (TBI) frequently precedes the onset of Alzheimer’s disease (AD) or AD-related dementia (ADRD), sometimes by decades. Multiple animal and human studies have linked microbiota composition and blood-brain barrier disruption with TBI, which would allow microbial material seeded into the bloodstream to gain access to the brain. Our project and its scientific rationale are based on evidence that microbial cells and fragments accumulate in the brain and contribute to neuropathology, leading to the behavioral and cognitive declines observed in humans with neurological diseases, including AD and ADRD. Our initial data demonstrate time-dependent accumulation of microbial fragments expressing the highly conserved microbial surface polysaccharide, poly-N-acetyl D-glucosamine (PNAG) in the brains of mice within days of receiving a closed head injury. Detection is accomplished with a fully human monoclonal antibody specific to microbial PNAG, which is not expressed by mammals, to detect microbial fragments in the brain. Immunizing AD mice with a PNAG-targeting vaccine led to prevention of cognitive deficits and removal of microbial PNAG associated with beta amyloid. The molecular and cellular basis for microbial material mediating neuronal dysfunction, and behavioral and cognitive decline in TBI and AD/ADRD pathology is unknown. Based on these data, we hypothesize that neuropathology is a result of inflammation driven by the persistence of undegraded microbiota-derived cells or cell fragments in the brains of affected humans and mice. Microbial fragments may gain access to the brain via disrupted mucosal and blood-brain barriers, or possibly via direct access from the oropharyngeal tract to the olfactory bulbs after TBI. These undegraded microbial remnants act as a focus leading to chronic inflammation. Preventing further accumulation of microbial factors with systemic antibody to PNAG, and/or removal and effective degradation of these microbial fragments in the brain, would reduce inflammation and tissue pathology resulting in spared cognitive and behavioral decline associated with TBI and AD/ADRD. Focus Area: Using these highly specific antibodies to microbial material, we will improve the understanding of the mechanisms, etiology, and potential therapeutic/treatment for symptoms of AD/ADRD after TBI by addressing the following questions: Specific Aim 1: Does TBI increase microbiota-derived microbial material access to brains in mice? Specific Aim 2: Can PNAG-specific antibodies impact TBI-mediated onset of AD/ADRD? Specific Aim 3: Do PNAG-specific antibodies enhance glial cell phagocytosis of PNAG and PNAG-Abeta or PNAG-tau composites? AD/ADRD affects ~6.2 million Americans aged 65 and older, resulting in 121,499 deaths from AD in 2019. AD is the sixth-leading cause of death in the United States and the fifth-leading cause of death among Americans aged 65 and older. Health care, long-term care, and hospice cost are estimated to be $355 billion for 2021. As yet there is no treatment for TBI or AD/ADRD and associated behavioral and cognitive decline. The onset of cognitive decline frequently follows a fall or infection, events that are linked with disruption of microbiota and increases in the mucosal and blood-brain barrier permeability. This would facilitate microbial cells and fragments gaining access to the brain. Being able to prevent these factors from accessing the brain could potentially decrease inflammation and behavioral and cognitive decline associated with AD/ADRD and TBI. Relevance to Military Health: The median age of U.S. male Veterans currently is 65, with the Veterans Health Administration (VHA) estimating dementia prevalence at 9.6%, like the 10.5% observed in the general population. Numerous studies have linked mild (2.3 times greater risk) and severe (4.5 times greater risk) TBI to the risk of developing dementias in later life and also as a precipitating factor in early onset de
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310261
Entities
People
- Michael J. Whalen
Organizations
- Massachusetts General Hospital
- United States Army