Alzheimer's Disease, Bone Health and Microbiome

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Abstract Alzheimer’s disease (AD), one of the most common causes of dementia, affects 35 million people worldwide. It is characterized by loss of cognitive function, formation of amyloid-β (APP-Aβ) deposits or plaques, and accumulation of intracellular microtubule-binding protein tau which leads to an abundance of neurofibrillary tangles (NFTs). AD also presents cellular signaling dysregulation, impairment of insulin signaling, chronic inflammation, synapse loss, cellular metabolism disorders, and oxidative stress. There is increasing evidence of a significant connection between AD and the gut (colon) microbiome where the bacteria carry out metabolic reactions and provide important nutrients and vitamins. Regulation of these nutrients can cause ripple effects throughout a host’s physiology which affect areas such as bone metabolism. For example, osteocalcin (OC) – a bone specific protein known to influence diverse physiological processes such as energy expenditure, glucose homeostasis and male fertility – crosses the blood brain barrier where it binds to neurons of the brainstem, midbrain, and hippocampus, and influences the synthesis of several neurotransmitters. Importantly, different functions of OC are regulated by the level of carboxylation; and level of OC carboxylation is governed by vitamin K derived from food and gut microbiome. The undercarboxylated form of OC was reported to be active in glucose metabolism in mice. Altered glucose metabolism and oxidative stress lead to formation of advanced glycation end-products (AGEs) that are linked to both the pathogenesis of AD and diabetes related skeletal fragility. Thus, the overall goal of this project is to investigate the interactions between brain, bone health and microbiome in the context of AD by determining the alterations in bone health and microbiome with AD progression (Specific Aim 1) and to investigate the mechanistic basis of such changes by establishing cause and effect through alterations of the microbial population (associated with production of vitamin K), uncarboxylated OC levels, or a combination of two and determining their impact on AD progression and bone health (Specific Aim 2). Our findings will establish the mechanistic underpinnings of the bone-brain-gut interactions, provide new insight into physiology of AD, and open new avenues for biomarker and therapeutic discovery to diagnose and/or alter the progression of AD and/or comorbidirites.