Maternal choline supplementation ameliorates Alzheimer's disease pathology by reducing brain homocysteine levels across multiple generations

The lack of effective treatments for Alzheimer's disease (AD) is alarming, considering the number of people currently affected by this disorder and the projected increase over the next few decades. Elevated homocysteine (Hcy) levels double the risk of developing AD. Choline, a primary dietary source of methyl groups, converts Hcy to methionine and reduces age-dependent cognitive decline. Here, we tested the transgenerational benefits of maternal choline supplementation (ChS; 5.0 g/kg choline chloride) in two generations (Gen) of APP/PS1 mice. We first exposed 2.5-month-old mice to the ChS diet and allowed them to breed with each other to generate Gen-1 mice. Gen-1 mice were exposed to the ChS diet only during gestation and lactation; once weaned at postnatal day 21, Gen-1 mice were then kept on the control diet for the remainder of their life. We also bred a subset of Gen-1 mice to each other and obtained Gen-2 mice; these mice were never exposed to ChS. We found that ChS reduced A beta load and microglia activation, and improved cognitive deficits in old Gen-1 and Gen-2 APP/PS1 mice. Mechanistically, these changes were linked to a reduction in brain Hcy levels in both generations. Further, RNA-Seq data from APP/PS1 hippocampal tissue revealed that ChS significantly changed the expression of 27 genes. These genes were enriched for inflammation, histone modifications, and neuronal death functional classes. Our results are the first to demonstrate a transgenerational benefit of ChS and suggest that modifying the maternal diet with additional choline reduces AD pathology across multiple generations.