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Ella Simonsen
Pronouns
They/Them/Theirs
Job Title
Assistant Researcher
Academic Rank
Department
Neurology
Authors
Ella Simonsen*, Caroline Wasen*, Danielle Leserve, Kusha Chopra, Millicent Ekwudo, Laura Cox, Howard Lee Weiner
Principal Investigator
Howard Lee Weiner
Research Category: Neurosciences
Tags
Alzheimer’s patients have a modulated gut microbiome and germ-free mice show reduced amyloid plaque levels, suggesting that AD microbiota contributes to pathology of the disease.
The effect of Alzheimer’s-related microbes on innate immunity and the function of microglia and macrophages remains unknown, specifically in relation to the ability to clear amyloid plaques and maintain neuronal health.
This study involved the depletion of the mouse microbiome through high-dose antibiotics, followed by repeated fecal microbiota transfers from two human AD patients and two age- and sex-matched healthy controls via oral gavage to APP/PS1 and wild-type mice. Within five months of treatment, spatial memory was examined using Y-maze test, and female mice colonized with AD-microbiota showed decreased frequency of spontaneous alternation, which indicates a lack of short-term memory. Seen through examination of immune function, the introduction of AD microbiome resulted in decreased CSF1R expression, a gene critical for microglial development. RNA sequence analysis showed the AD microbiota altered genes related to microglial response to bacteria, phagocytosis, cytokine regulation, transcription factor activity, and regulation of apoptosis. Neurodegenerative microglia and neurotoxic effects were upregulated, and neuroprotective effects were downregulated.
These findings suggest that AD microbiota impairs spatial memory and induces a neurodegenerative phenotype of microglia.
The microbiome, or bacteria in the gut, affects the development of Alzheimer’s disease; however, we do not yet know how bacteria associated with AD affect the immune cells in the brain and lessen their ability to maintain neuronal health.
We studied mice that have been genetically modified to develop Alzheimer’s disease, and started by depleting their original microbiome using antibiotics. Then, the mice were given human microbiome from AD patients and healthy controls over the course of 5 months so that their gut bacteria would resemble that of AD patients. This allowed study of how AD microbiota affect the development and pathology of AD.
We found that the transfer of bacteria from female AD patients into female mice lead to decreased memory. AD bacteria also lead to change in the expression of various genes related to the development of immune cells in the brain. Microglia, which are responsible for maintenance of cells in the brain, had a gene expression indicating that they were under developed, incapable of clearing debris from the brain, unable to regulate cell death, and even became neurotoxic.
These findings suggest that AD microbiota impairs spatial memory and induces a neurodegenerative phenotype of microglia.
