Benefits of Maternal Choline Supplementation on Aged Basal Forebrain Cholinergic Neurons (BFCNs) in a Mouse Model of Down Syndrome and Alzheimer's Disease

Document Type

Article

Abstract

Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer's disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD.

Keywords

Alzheimer’s disease, Down syndrome, RNA-sequencing, aging, choline acetyltransferase, laser capture microdissection, maternal choline supplementation, trisomy

Medical Subject Headings

Animals; Down Syndrome (metabolism, pathology, genetics, drug therapy); Choline (pharmacology, administration & dosage); Cholinergic Neurons (drug effects, metabolism, pathology); Alzheimer Disease (metabolism, pathology, genetics); Female; Disease Models, Animal; Mice; Basal Forebrain (metabolism, drug effects, pathology); Dietary Supplements; Pregnancy; Male; Humans

Publication Date

8-5-2025

Publication Title

Biomolecules

E-ISSN

2218-273X

Volume

15

Issue

8

PubMed ID

40867575

Digital Object Identifier (DOI)

10.3390/biom15081131

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