Dietary choline intake is necessary to prevent systems‐wide organ pathology and reduce Alzheimer's disease hallmarks

Abstract

There is an urgent need to identify modifiable environmental risk factors that reduce the incidence of Alzheimer's disease (AD). The B‐like vitamin choline plays key roles in body‐ and brain‐related functions. Choline produced endogenously by the phosphatidylethanolamine N‐methyltransferase protein in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. ~90% of Americans do not reach the recommended daily intake of dietary choline. Thus, it's imperative to determine whether dietary choline deficiency increases disease outcomes. Here, we placed 3xTg‐AD, a model of AD, and non‐transgenic (NonTg) control mice on either a standard laboratory diet with sufficient choline (ChN; 2.0 g/kg choline bitartrate) or a choline‐deficient diet (Ch‐; 0.0 g/kg choline bitartrate) from 3 to 12 (early to late adulthood) months of age. A Ch‐ diet reduced blood plasma choline levels, increased weight, and impaired both motor function and glucose metabolism in NonTg mice, with 3xTg‐AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, elevated soluble and insoluble Amyloid‐β and Thioflavin S structures, and tau hyperphosphorylation at various pathological epitopes in the hippocampus and cortex of 3xTg‐AD Ch‐ mice. To gain mechanistic insight, we performed unbiased proteomics of hippocampal and blood plasma samples. Dietary choline deficiency altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, dietary choline deficiency altered protein networks associated with insulin metabolism, mitochondrial function, inflammation, and fructose metabolic processing. Our data highlight that dietary choline intake is necessary to prevent systems‐wide organ pathology and reduce hallmark AD pathologies.

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

“…Tg2576 mice also lack tau pathology. However, MCS has now demonstrated structural/functional benefits in several AD-relevant models, namely Tg2576 (this report), APP/PS1 (Alldred et al 2021;Dave et al 2023), Ts65Dn (Velazquez et al 2013;Powers et al 2016;Strupp et al 2016;Powers et al 2017;Alldred et al 2021;Alldred et al 2023) and 3xTg mice (Dave et al 2023). Moreover, increasing evidence suggests that humans with AD have low serum choline and are improved by dietary choline (Dave et al 2023;Judd et al 2023a;.…”

“…In Alzheimer's disease (AD), changes to the diet have been recommended (Bourre 2006;Power et al 2019;Mao et al 2021;Lobo et al 2022), including MCS (Strupp et al 2016;Velazquez et al 2020;Dave et al 2023;Judd et al 2023a;. One reason for the recommendation is that serum levels of choline are low in individuals with AD (Dave et al 2023;Judd et al 2023b).…”

Basal forebrain cholinergic neurons are vulnerable in a mouse model of Down syndrome and their molecular fingerprint is rescued by maternal choline supplementation

“…A recent study showed Grin2A protein expression significantly decreases in the absence of choline, which is further exacerbated in an AD mouse model, suggesting this defect is due to alterations of postsynaptic protein concentrations secondary to insufficient choline. 128 Previous studies have shown differential synaptic and peri-or extra-synaptic localization of these subunits, which can be exchanged by lateral diffusion to finely modulate synaptic strength. 129 Perhaps even more intriguing, ratio imbalances between Grin2a and Grin2b increased cognitive decline and activation of Grin2b containing receptors has been linked to AD due to glutamate excitotoxicity.…”

“…Upregulation of NMDA receptor subunits Grin2a and Grin2b is found in trisomic mice with Grin2a significantly reduced in disease diet, which was corroborated by qRT‐PCR, and Grin2b partially attenuated. A recent study showed Grin2A protein expression significantly decreases in the absence of choline, which is further exacerbated in an AD mouse model, suggesting this defect is due to alterations of postsynaptic protein concentrations secondary to insufficient choline 128 . Previous studies have shown differential synaptic and peri‐ or extra‐synaptic localization of these subunits, which can be exchanged by lateral diffusion to finely modulate synaptic strength 129 .…”

Castration Model Illuminates Sex Differences in Healthy Aging: Insights from Metabolome and Transcriptome Analyses

“…taurodeoxycholic acid [39], nicotinamide [40], ascorbic acid (vitamin C) [41], Dpantothenic acid (vitamin B5) [42,43] and choline [44] (Figure 4C). Similar to shamF, casM mice also showed an enrichment of anti-oxidative metabolites likely derived from plant-based foods, including ganoderenic acid C [45], oleuropeic acid [46], fasciculol C [47], graveoline [48] (Figure 4C).…”