PROJECT SUMMARY In recent years, it has become apparent that a “gut-brain” axis exists where communication occurs between the gut, its microbiota, the immune system and the brain. Although not fully understood, this axis has a major role in the onset and severity of many neurodegenerative diseases (NDD). In direct response to PAR-19-070, we propose to study the role of the gut-brain axis in Alzheimer’s disease (AD). AD is a common, progressive and devastating NDD characterized by memory impairment and cognitive decline. The most prominent pathological hallmarks of the disease are the extracellular accumulation of amyloid β (Aβ) peptides in the form of plaques. Non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. A growing body of evidence suggests that intestinal bacteria produces amyloid-like proteins that form biofilms. Loss of gut barrier integrity leads to bacterial breach and bacterial amyloid translocation that potentially causes inflammation and accelerate central-Aβ pathology that then contribute to NDD progression from gut to brain. Gut inflammation can also impair nutrient absorption. B12 influences myelin homeostasis and its malabsorption accelerates brain amyloidosis. Myelin loss and the inability of the oligodendrocytes, the cells responsible for the production and maintenance of myelin, to repair myelin damage, are central features of AD and are associated with dementia. B12 biosynthesis is confined to certain bacteria. Luminal B12 is absorbed by gut epithelial receptors and stored as transcobalamine-B12 complex (tBC). For B12 to actively take part in biological processes, it needs to be stored in the form of tBC. The pathologic cascade linking gut pathology to Aβ deposition is not understood. We will develop the idea that early acute gut inflammation leads to impaired gut integrity and B12 malabsorption leading to accelerated central-Aβ pathology. It is this “loss of gut barrier integrity” that sustains an environment conductive for onset and progression of Aβ aggregation related dementias. We propose to test the following hypothesis that gut dysfunction precedes amyloid-β aggregation in the AD brain. (i) Restoring receptor- mediated B12 absorption and (ii) improving integrity of the gut by “early” beneficial bacterial therapy will lead to reduced Aβ aggregation “later” in the transgenic AD mice brain. In Aim 1, we will determine if gut inflammation early in life accelerates Aβ aggregation in the brain. If brain Aβ aggregation and disease progression are secondary to early gut abnormalities, then creating gut inflammation early in life will lead to loss of gut integrity, increased bacterial breach and subsequent bacterial amyloid translocation and earlier brain Aβ aggregation. In Aim 2, we will determine if B12 receptor loss and/or B12 malabsorption leads to impaired myelination and earlier Aβ aggregation. In Aim 3, we will determine if preventing gut dysfunction and restoring gut homeostasis with a beneficial bacterium (a B12 producer) improves absorption, gut integrity and delays the onset or progression of AD. These studies represent a “translatable” foundation for the potential treatment of neurodegenerative diseases in humans

PROJECT NARRATIVE: The gut-brain axis has recently been identified as a key player in the pathogenesis of neurodegenerative diseases (NDD), most notably in Alzheimer’s disease (AD). A growing body of evidence suggests that dysfunctional gut and its microbe-derived factors may contribute to central amyloid pathogenesis. These studies will provide novel and alternative strategies for prevention/ intervention in AD and other dementias.