Winslow, W. | bioRxiv Science

bioRxiv2023

Low circulating choline, a modifiable dietary factor, is associated with the pathological progression and metabolome dysfunction in Alzheimers disease.

Most Americans ([~]90%) are deficient in dietary choline, an essential nutrient. Associations between circulating choline and pathological progression in Alzheimers disease (AD) remain unknown. Here, we examined these associations and performed a metabolomic analysis in blood serum from severe AD, moderate AD, and healthy controls. Additionally, to gain mechanistic insight, we assessed the effects of dietary choline deficiency (Ch-) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice. In humans, we found AD-associated reductions in choline, its derivative acetylcholine (ACh), and elevated pro-inflammatory cytokine TNF. Choline and ACh were negatively correlated with Plaque density, Braak stage, and TNF, but positively correlated with MMSE and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were associated with choline levels. In mice, Ch-paralleled AD severe, but Ch+ was protective. In conclusion, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of dietary choline consumption to offset disease.

pathology↗

bioRxiv2022

Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimers disease hallmarks

Evidence suggests that environmental factors may contribute to Alzheimers disease (AD). The B-like vitamin choline plays key roles in body- and brain-related functions. Choline produced endogenously by the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. [~]90% of Americans dont reach the recommended daily choline intake. Thus, its imperative to determine whether dietary deficiency increases disease outcomes. Here, we placed 3xTg-AD, a model of AD, and non-transgenic (NonTg) control mice on either a sufficient choline (ChN) or choline deficient (Ch-; choline deficiency) diet from 3 to 12 (early to late adulthood) months of age. Ch- reduced plasma choline and acetylcholine levels, increased weight, and impaired both glucose metabolism and motor function in NonTg, with 3xTg-AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, and elevated Amyloid-{beta} and phosphorylated tau in the hippocampus and cortex of 3xTg-AD Ch- mice. Unbiased proteomic analyses revealed Ch- altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, Ch- altered protein networks associated with insulin metabolism, mitochondrial function, and inflammation. Collectively, our data highlight that dietary choline intake is necessary to prevent systems-wide organ pathology and reduce AD hallmark pathologies.

neuroscience↗