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

Chartampila, E.; Elayouby, K. S.; Leary, P.; LaFrancois, J. J.; Alcantara-Gonzalez, D.; Jain, S.; Gerencer, K.; Botterill, J. J.; Ginsberg, S. D.; Scharfman, H.

doi:10.1101/2023.05.12.540428

bioRxiv · 10.1101/2023.05.12.540428

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

Chartampila, E.·Elayouby, K. S.·Leary, P.·LaFrancois, J. J.·Alcantara-Gonzalez, D.·Jain, S.·Gerencer, K.·Botterill, J. J.·Ginsberg, S. D.·Scharfman, H.

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Abstract

Maternal choline supplementation (MCS) improves cognition in Alzheimers disease (AD) models. However, effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice are generalized EEG spikes (interictal spikes; IIS). IIS also are common in other mouse models and occur in AD patients. Im mouse models, hyperexcitability is also reflected by elevated expression of the transcription factor {Delta}FosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. Therefore we studied {Delta}FosB expression in GCs. We also studied the the neuronal marker NeuN within hilar neurons of the DG because other studies have reduced NeuN protein expression is a sign of oxidative stress or other pathology. This is potentially important because hilar neurons regulate GC excitability. Tg2576 breeding pairs received a diet with a relatively low, intermediate or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC {Delta}FosB expression was reduced, and NeuN expression was restored. Using the novel object location task, spatial memory improved. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC {Delta}FosB protein expression. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, {Delta}FosB and spatial memory in an animal model of AD.

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Chartampila, E., Elayouby, K. S., Leary, P., LaFrancois, J. J., Alcantara-Gonzalez, D., Jain, S., Gerencer, K., Botterill, J. J., Ginsberg, S. D., Scharfman, H.. 2023-05-12. Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer's disease.. https://doi.org/10.1101/2023.05.12.540428

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