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Perinatal Choline Supplementation Promotes Resilience Against Progression of Alzheimer's Disease-Like Brain
Thomas A Bellio1, Andre Krunic1,2, Mary S Campion1
1Department of Pathology and Laboratory Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA.
Insights
Perinatal choline supplementation (PCS) in Alzheimer
Area of Science:
- Neuroscience
- Genetics
- Nutritional Science
Background:
- Alzheimer's disease (AD) lacks effective treatments and prevention strategies.
- Previous studies indicated choline supplementation improves cognitive deficits and reduces amyloidosis in AD mouse models.
Purpose of the Study:
- To investigate transcriptomic changes in AppNL-G-F AD model mice.
- To determine if perinatal choline supplementation (PCS) can attenuate these transcriptomic abnormalities.
Main Methods:
- AppNL-G-F and wild-type mice dams received control or choline-supplemented diets pre-mating through weaning.
- Offspring hippocampus and cerebral cortex RNA sequencing was performed at multiple ages (3, 6, 9, 12 months).
Main Results:
- AD model mice on a control diet showed age-dependent increases in inflammation-related gene expression and decreases in neuronal function genes.
- PCS in AD model mice upregulated synaptic and GABAergic function genes while downregulating inflammation-related genes.
- These gene expression changes in PCS-treated mice counteracted the effects of the AD genotype.
Conclusions:
- Perinatal choline supplementation can normalize gene expression related to neuronal function and inflammation in an AD mouse model.
- Choline-protected gene expression changes correlated with human AD pathology markers.
- Adequate choline intake may represent a potential preventive strategy for Alzheimer's disease.
Abstract:
Alzheimer's disease (AD)-the leading cause of dementia-has no cure, inadequate treatment options, and a limited understanding of prevention measures. We have previously shown that perinatal dietary supplementation with the nutrient choline ameliorates cognitive deficits and reduces amyloidosis across the brain in AppNL-G-F AD model mice. Here, we analyzed transcriptomic abnormalities in these mice and tested the hypothesis that they may be attenuated by perinatal choline supplementation (PCS). Wild-type (WT) and AppNL-G-F dams consumed a diet containing 1.1 (control) or 5 g/kg (supplemented) of choline chloride from 2 weeks prior to mating until weaning. At 3, 6, 9, or 12 months of age, the offspring RNA was sequenced in the hippocampus and cerebral cortex. As compared to WT, the AppNL-G-F mice reared on the control diet had age-dependent upregulation of expression of mRNAs and lncRNAs related to inflammation and reduced expression of mRNAs related to neuronal function. As compared to AppNL-G-F mice on the control diet, PCS AppNL-G-F mice increased expression of synaptic genes and downregulated inflammation-related genes starting at 6 months in the cortex; increased expression of GABAergic function and ATP metabolism genes, and decreased expression of inflammatory genes in the hippocampus at 12 months. These changes counteracted the effects of AppNL-G-F genotype seen in mice on the control diet. The expression of many of these choline-protected genes correlated with clinical dementia rating, inflammation, and tauopathy in human postmortem dorsolateral prefrontal cortex AD samples, indicating their relevance to the disease process. The results suggest that adequate choline intake could be a preventive strategy for AD.
