Maternal Choline Supplementation Improves Cognitive and Neuronal Outcomes in a Mouse Model of Alzheimer's Disease

แนวคิดหลัก

Maternal choline supplementation can improve cognitive function, neuronal hyperexcitability, and neuronal markers in a mouse model of Alzheimer's disease, while low choline levels can have adverse effects.

บทคัดย่อ

The study investigated the effects of maternal choline supplementation (MCS) on cognitive function, neuronal hyperexcitability, and neuronal markers in a mouse model of Alzheimer's disease (AD), the Tg2576 mouse. Tg2576 breeding pairs were fed diets with low, intermediate, or high choline concentrations, and the offspring were then tested.
Key findings:

Offspring of mice fed the high choline diet showed reduced interictal spike (IIS) frequency, decreased granule cell ΔFosB expression (a marker of neuronal hyperexcitability), and restored NeuN expression (a neuronal marker) in the dentate gyrus. These mice also exhibited improved spatial memory performance.
In contrast, offspring exposed to the low choline diet had increased mortality, the weakest hilar NeuN immunoreactivity, and the greatest granule cell ΔFosB expression, although their IIS frequency was surprisingly low.
The intermediate choline diet did not prevent cognitive deficits or neuronal changes in Tg2576 mice.
The high choline diet improved object location memory in both wild-type and Tg2576 mice at 3 and 6 months of age, while the low and intermediate choline diets impaired performance.
The high choline diet also led to increased time spent exploring objects during the behavioral tasks, which may have contributed to the improved memory.

These results provide evidence that a diet high in choline early in life can improve outcomes in an AD mouse model, while low choline can have mixed effects. This is the first study to demonstrate that dietary choline can regulate hyperexcitability, hilar neurons, ΔFosB, and spatial memory in an AD animal model.

สถิติ

Tg2576 mice exposed to the high choline diet showed reduced interictal spike (IIS) frequency compared to those fed the low or intermediate choline diets.
Tg2576 mice exposed to the high choline diet had decreased granule cell ΔFosB expression compared to those fed the low choline diet.
Tg2576 mice exposed to the high choline diet had restored NeuN expression in the dentate gyrus hilus compared to those fed the low or intermediate choline diets.
Tg2576 mice exposed to the low choline diet had increased mortality compared to those fed the high choline diet.

คำพูด

"In offspring of mice fed the high choline diet, IIS frequency declined, GC ΔFosB expression was reduced, and NeuN expression was restored."
"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 ΔFosB protein expression."

ข้อมูลเชิงลึกที่สำคัญจาก

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

by Chartampila,... ที่ www.biorxiv.org 05-12-2023

https://www.biorxiv.org/content/10.1101/2023.05.12.540428v4

สอบถามเพิ่มเติม

How might the effects of maternal choline supplementation on neuronal hyperexcitability and markers translate to cognitive and functional outcomes in humans with Alzheimer's disease?

The effects of maternal choline supplementation on neuronal hyperexcitability and markers, such as reduced expression of ΔFosB and restoration of NeuN levels, could potentially translate to improved cognitive and functional outcomes in humans with Alzheimer's disease. In the context of Alzheimer's disease, neuronal hyperexcitability is a common feature that can lead to cognitive impairments and memory deficits. By reducing hyperexcitability and restoring neuronal markers associated with healthy brain function, maternal choline supplementation may help improve cognitive abilities, memory retention, and overall brain health in individuals with Alzheimer's disease.
Choline is a vital nutrient that plays a crucial role in brain development and function. It is a precursor to acetylcholine, a neurotransmitter essential for memory and learning. Therefore, by enhancing choline levels through supplementation, the brain may have the necessary resources to maintain proper neurotransmission, synaptic plasticity, and overall cognitive function. Additionally, the reduction in hyperexcitability, as indicated by decreased IIS frequency and ΔFosB expression, may contribute to a more stable and balanced neuronal activity, which is crucial for optimal cognitive performance.
In humans with Alzheimer's disease, where choline levels are often found to be low, supplementation could potentially counteract the detrimental effects of choline deficiency on brain health. Improved neuronal function, reduced hyperexcitability, and restored neuronal markers may collectively lead to enhanced cognitive abilities, better memory retention, and overall improved functional outcomes in individuals with Alzheimer's disease.

What are the potential mechanisms by which low choline levels during early life development could lead to the mixed effects observed in this study, such as reduced IIS frequency but impaired spatial memory and neuronal markers?

Low choline levels during early life development can have significant impacts on brain development and function, potentially leading to the mixed effects observed in the study. Choline is a critical nutrient that is essential for various processes in the brain, including neurotransmitter synthesis, membrane structure, and signaling pathways. When choline levels are insufficient, several mechanisms may contribute to the observed effects:

Neuronal Hyperexcitability: Low choline levels can disrupt neurotransmitter synthesis, particularly acetylcholine, which is essential for regulating neuronal excitability. Reduced choline availability may lead to imbalances in neurotransmission, resulting in increased neuronal hyperexcitability and the generation of interictal spikes (IIS).

Impaired Synaptic Plasticity: Choline deficiency can impact synaptic plasticity, the ability of synapses to strengthen or weaken over time in response to activity. Altered synaptic plasticity can impair learning and memory processes, leading to deficits in spatial memory tasks.

Neuronal Health: Choline is crucial for maintaining neuronal health and integrity. Insufficient choline levels may compromise neuronal structure and function, leading to changes in neuronal markers like NeuN expression. Reduced NeuN levels are often associated with neuronal damage or dysfunction, which can further contribute to cognitive impairments.

Oxidative Stress and Inflammation: Choline deficiency can increase oxidative stress and inflammation in the brain, which are known to negatively impact neuronal function and cognitive outcomes. These processes may further exacerbate the effects of low choline levels on brain health and function.

The combination of these mechanisms may explain the mixed effects observed in the study, where reduced IIS frequency but impaired spatial memory and neuronal markers were observed in mice exposed to relatively low choline levels during early life development.

Given the complex interplay between diet, neuronal function, and cognitive outcomes, what other dietary or lifestyle factors might interact with choline to influence Alzheimer's disease progression and could be investigated in future studies?

Several dietary and lifestyle factors may interact with choline to influence Alzheimer's disease progression and could be explored in future studies:

Omega-3 Fatty Acids: Omega-3 fatty acids, particularly docosahexaenoic acid (DHA), are essential for brain health and cognitive function. Studies have shown that a diet rich in omega-3 fatty acids may have neuroprotective effects and could potentially interact with choline to improve cognitive outcomes in Alzheimer's disease.

Antioxidants: Antioxidants, such as vitamin E and vitamin C, play a crucial role in reducing oxidative stress and inflammation in the brain. Combining choline supplementation with antioxidant-rich foods or supplements may have synergistic effects on brain health and cognitive function.

Physical Activity: Regular physical exercise has been associated with improved cognitive function and reduced risk of neurodegenerative diseases. Investigating the interaction between choline supplementation and physical activity in Alzheimer's disease could provide valuable insights into holistic approaches to brain health.

Mediterranean Diet: The Mediterranean diet, rich in fruits, vegetables, whole grains, and healthy fats, has been linked to cognitive benefits and reduced risk of Alzheimer's disease. Exploring the combined effects of choline and a Mediterranean-style diet on brain health could offer a comprehensive approach to disease prevention and management.

Stress Management: Chronic stress and elevated cortisol levels have been associated with cognitive decline and neurodegeneration. Strategies for stress management, such as mindfulness practices or relaxation techniques, could complement choline supplementation in promoting brain health and cognitive resilience.

Investigating the interactions between choline and these dietary and lifestyle factors in Alzheimer's disease progression could provide valuable insights into multifaceted approaches to disease management and prevention.