Gut Microbiome-Mediated Shifts in Amyloid Beta Deposition in a Humanized Alzheimer’s Disease Mouse Model

2017, 2019

2019

Evidence is accumulating of an extensive bidirectional relationship between the gut microbiome and the brain. This interaction has important implications for brain health. The gut and microbiota modulate brain pathways that, in turn, influence gastrointestinal functioning, as well as the composition and functioning of the enteric microbiome. This complex interaction is referred to as the microbiota-gut-brain axis. Our study aims to investigate whether deposition of amyloid beta plaques in the brain can be modulated by changing the microbiota-gut-brain axis.

2017

Microorganisms of the human gastrointestinal tract are collectively referred to as the gut microbiota or microbiome. More than a century ago, Nobel laureate Elie Metchnikoff first proposed manipulation of the gut microbiome as a possible treatment for neurological disorders. However, only recently have procedures emerged that allow the microbiome to be reproducibly changed in ways that provide reliable and specific benefits for patients with neurological disease.

Among the most successful approaches has been fecal transplantation. In fecal transplantation, the gut microbiota from healthy subjects is transferred to patients suffering disease. Our own studies, and recent findings reported by other laboratories, suggest cerebral amyloid deposition, the hallmark pathology for Alzheimer’s disease (AD), may be among the brain pathologies linked to gut microbiota. In this study, we propose to extend our study of the connection between AD amyloidosis and the gut microbiome. Previously, we have shown the gut microbiome of genetically modified AD mice is shifted toward abnormal bacterial species linked to health disorders. In this study, we propose to extend our investigations and test whether fecal transplants that replace abnormal amyloid-associated gut microbiota with the microbiome of normal mice can reduce AD amyloidosis.

Our study will use humanized AD mice that recapitulate mechanisms that normally regulate amyloid generation in humans. In previous AD mouse models, amyloid-generating pathways are artificially maintained at abnormally high levels. We also will investigate whether gut microbial metabolic products known to travel to
the brain are responsible for modulating amyloidosis. Confirmation that gut microbiome manipulation may be able to delay the onset of AD amyloid pathology would be a major advance for the field. Moreover, it would open the possibility of adapting existing approved medical procedures for the treatment, and possible diagnosis, of AD. To that end, we hope to include experiments to screen ingestible agents that could be helpful in slowing cerebral deposition of harmful amyloid.


Funding to Date

$500,000

Focus

Microbiome, Translational Research

Researchers

Deepak Kumar Vijaya Kumar, Ph.D.