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Project Topic
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With the increasing number of patients diagnosed with dementia, including Alzheimer’s disease (AD), unraveling the
cellular and the molecular mechanisms involved in its pathogenesis and understanding how non-pharmacological
treatment can benefit brain health is crucial. Evidence from human and mouse studies indicate that the intestinal
microbiota, among other environmental factors, is tightly associated with controlling the innate and adaptive immune
system which may influence AD development. Reduced contact with microbiota or changes in its composition, due
to excessive hygiene or western-like diets low in fiber, early in infancy can imprint inappropriate immune system
maturation with long-lasting consequences on the function of central nervous system (CNS). We recently uncovered
that the gut microbiota upon solid food introduction at weaning induces an immune response in the intestine, termed
“weaning reaction”, which prevents impaired immune system reactivity in adult mice. Inhibition of this weaning
reaction generation imprints the immune system to develop severe inflammation later in life, a phenomenon we called
“pathological imprinting”. Our preliminary results indicate that the gut microbiota-induced weaning reaction reduces
the pathological susceptibility to develop AD in adult mice. As the maturation and function of neurons and microglia,
the tissue-resident macrophages of the CNS, are steered by gut bacteria-derived molecules post-birth, it is plausible
that adult AD development is impacted by pathological immune and neuronal imprinting mediated by weaning
reaction.
Determining the cellular mechanisms driving pathological imprinting, defining the nature of such imprinting and how
to manipulate it by diet-induced microbial changes will provide fundamental knowledge for early prevention,
identification of adults at high risk to develop AD, and establishment of new therapies to treat AD. Since ketogenic
diet, physical exercise and cognitive training prior to AD development have been reported to modulate the gut
microbiota, shape the immune system, reduce neuronal apoptosis and promote neurotrophic signaling with beneficial
effects on brain function, it is conceivable that those non-pharmacological factors can revert the early life pathological
imprinting. Here, the results from the in vivo models will be verified in human cell culture systems as well as in human
AD brains.
In this project, we will combine the effort of five multidisciplinary groups across neurology, immunology, microbiology
and cognitive memory and use cutting-edge omics technologies, translational approaches with human tissues and
gnotobiotic zebrafish and mouse models to 1) define dietary and microbial components early in life dictating the
intestinal immune reaction and their causal role on the CNS pathological imprinting and AD development later in life,
and 2) unravel the cellular and molecular pathways by which ketogenic feeding, physical exercise and cognitive
training in adult can revert the AD pathological imprinting. These results will pave the way for the generation of
improved approaches to prevent and/or treat AD in later adulthood.
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