In recent years, it has become apparent that a ?gut-brain? axis exists where communication occurs between the gut, its microbiota, and the brain. Although not fully understood, this axis has a major role in the onset and severity of many neurological diseases. In direct response to PAR-17-029, we propose to study the gut-brain axis in aging and in a model of cerebral amyloid angiopathy (CAA), a neurodegenerative condition that is characterized by the deposition of toxic amyloid-beta aggregates into the basement membrane of brain arterioles and capillaries, leading to recurrent stroke, cerebral hemorrhage and cognitive decline. Results will be compared to an animal model that demonstrates both parenchymal and vascular amyloid deposition (Tg2576) to determine if the microbiome has a preferential effect on vascular amyloid. We will develop the idea that the gut microbiota constitutes a fundamental source for the initiation and maintenance of inflammation associated with aging. It is this ?age-inflamed brain? that sustains an environment conducive for the onset and progression of CAA and other dementias. We propose to test the following hypotheses. (1) Age-related dysbiosis initiates and sustains brain inflammation in WT mice through the gut-brain axis, which can be reversed by manipulation of the biome. (2) Preventing dysbiosis delays the onset of amyloid deposition in animal models and restoration of a balanced microbiome after the onset of disease can decrease severity, behavioral deficits, and slow disease progression.
In Aim 1, we will determine if neuroinflammation can be decreased in aged WT mice by altering the microbiome. If age-related dysbiosis is responsible for enhanced neuroinflamation, then creating a ?young? microbiome in aged mice should reduce brain and systemic inflammation, this will be assessed with several methods including flow cytometry and immunohistochemistry.
In Aim 2, we will determine if bacteria and bacterial components translocate the gut epithelial barrier, gain access to the systemic circulation, and ultimately traffic to the brain to induce neuroinflammation in aged WT mice. We will determine if aged-related dysbiosis increases translocation of labeled bacteria and bacterial toxins/metabolites from the gut to brain.
In Aim 3, we will determine if preventing dysbiosis delays the onset of amyloid deposition and behavioral deficits in animal models. We will use fecal microbiota transfer to alter the biome in two lines of mice, one that deposits amyloid primarily in the parenchyma (neurons), and the other that preferentially deposits amyloid in the cerebral blood vessels and models CAA. This latter strain may be more sensitive to biome manipulation as the neurovascular niche may be the ?first line? of cells exposed to bacterial antigens or metabolites, and the first to generate an immune response. As sex differences are present in longevity/aging, inflammation and immunity, vascular disease, dementia, and the biome, all studies will be performed in both sexes. These studies represent a ?translatable? foundation for the potential treatment of age-related neurodegenerative diseases in humans.
Aging is an important risk factor for the development of many chronic illnesses that increase functional disability and limit survival, including dementia. These diseases are becoming increasingly prevalent in the US with the growth of our elderly population. The ?microbiota-gut-brain axis? changes with age. This work will examine how manipulating the microbiome, the population of bacteria residing in the gut, influence the onset and progression of cerebral amyloid angiopathy (CAA), a neurodegenerative condition. Most importantly, these studies will provide novel strategies for prevention and intervention in CAA and other dementias of aging.
|Spychala, Monica S; Venna, Venugopal Reddy; Jandzinski, Michal et al. (2018) Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome. Ann Neurol 84:23-36|