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Benefits of Maternal choline supplementation on aged basal forebrain cholinergic neurons in a mouse model of Down syndrome and Alzheimer’s disease

ABSTRACT: Down syndrome (DS) stemming from triplication of chromosome 21 causes intellectual disability, with early onset of Alzheimer’s disease (AD) pathology in mid-life. Early intervention studies to reduce cognitive impairments and onset of pathology are lacking. One such treatment, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodegenerative and neurodevelopmental diseases in rodent models including DS mouse models. Basal forebrain cholinergic neuron (BFCN) degeneration and enlarged endosomal phenotype is reduced due to maternal choline supplementation (MCS) in a mouse model of Down Syndrome (Ts65Dn) with concomitant beneficial behavioral effects. However, the underlying mechanisms and gene expression alterations during aging and BFCN degeneration are understudied. We postulate cellular mechanisms driving these alterations will be elucidated with novel therapeutic targets identified by examining the modulation in MCS treated aged DS mice. Immunohistochemical ChAT staining in the medial septal/ventral diagonal band area of the basal forebrain in ~11 MO DS and control (2N) mice with and without MCS was performed. Approximately 500 cholinergic positive neurons per animal were microisolated for RNA-sequencing. Bioinformatic analysis elucidated gene expression alterations in the aged DS mouse model compared to controls which were attenuated by MCS treatment in the DS and control animals, including cognitive impairment and NAD signaling pathway. In conclusion, MCS treatment shows moderate effects on gene expression in aged BFCNs, indicating that MCS prolongs the healthspan in this DS mouse model, but does not eliminate disease onset.

ORGANISM(S): Mus musculus

PROVIDER: GSE296095 | GEO | 2025/08/05

REPOSITORIES: GEO

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Project description:Individuals with Down syndrome (DS) exhibit neurological deficits throughout the lifespan culminating in Alzheimer’s disease (AD) pathology and cognitive impairment during early mid-life. At the cellular level, dysregulation in neuronal gene expression has been shown in the human brain and mouse models of DS. However, RNA- sequencing (RNA-Seq) analysis of genomic neuronal expression in the hippocampus have been limited, without separation of neuronal populations based on circuitry inputs. We postulate spatially characterized hippocampal excitatory neurons will present with unique gene expression patterns due in part to unique circuitry inputs in the DS mouse model. Here, we combined laser capture microdissection (LCM) to isolate individual neuron populations with low input RNA-seq analysis to determine gene expression analysis of three excitatory neuron populations from the rostral hippocampus. We utilized the Ts65Dn mouse model of DS at the start of degeneration (6MO) to query gene expression profiles of CA1 and CA3 pyramidal neurons, along with dentate gyrus (DG) granule cells. The hippocampal structure is critical for learning and memory, with significant impairments of both behavior and synaptic activity in the DS mouse model which undergo degeneration during aging. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in the DS mice. Bioinformatic queries revealed unique vulnerabilities and mechanistic differences which coincide with onset of degeneration in the Ts65Dn model of DS/AD. These unique vulnerabilities may underlie the degenerative phenotype in DS, suggesting precision medicine targeting individual populations of neurons may be required for therapeutic advancement. We further analyzed maternal choline supplementation in each neuronal population, treating the dams during gestation through weaning with choline normal diet (1.1g/kc choline chloride) or choline suppmentation (5.0g/kg choline chloride) in the normal (AIN-76A) mouse chow from Dyets. At weaning (postnatal day 21), pups were aged on a choline normal diet until 6 months old.

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Benefits of Maternal choline supplementation on aged basal forebrain cholinergic neurons in a mouse model of Down syndrome and Alzheimer’s disease

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