The role of brain support cells in energy production in Alzheimer’s

Alzheimer’s disease (AD) is the most common progressive dementia with two main forms, familial (fAD) and sporadic (sAD). Familial AD is inherited, typically developing at a younger age, and accounts for 5-10% of all cases. Most cases are sporadic, occurring at a later onset without a clear inheritance or causation pattern. While the exact cause of AD in both fAD and sAD remains unclear, emerging research shows the brain’s metabolism is disrupted.

Metabolism is how brain cells take dietary nutrients from the bloodstream to produce and store energy enabling cells to function. Two types of brain cells, neurones, and astrocytes, work closely together during brain metabolism. Astrocytes play an important role in protecting and supporting neurones, including providing energy sources such as lactate, which neurones can take up and metabolise. Both cell types rely on mitochondria, which act as the power plant of the cell. Mitochondria aid energy production by converting nutrients such as glucose (sugar) into chemicals which give the cells fuel. In converting sugar into fuel, a molecule called Hexokinase 1 (HK1) is needed to help the mitochondria process sugar. In AD, a dysfunction in HK1 means that astrocytes struggle to use sugar effectively, reducing energy production. This lower energy production has been shown to impact brain functions such as memory and thinking, key symptoms of AD.

Why is the study important?

Defects in astrocyte sugar processing affect both neighbouring astrocytes and neurones in the brain. Disruption of metabolism in astrocytes has been shown in the early stages of AD. This study increases the knowledge of how astrocyte HK1 functions in individuals with AD, providing more insight into the potential role of HK1 as a therapeutic target for AD.

What did the authors do and how did they do it?

The authors investigated the number of mitochondria and sugar processing in astrocytes, how decreases in HK1 function harm energy processing, and if increasing the levels of HK1 would affect mitochondria and sugar processing function. To do this, the authors used astrocytes derived healthy controls, and people living with AD; sporadic AD (sAD) and familial (inherited) AD. To achieve this, skin cells were taken, and by using a cocktail of chemicals, the skin cells were turned into astrocytes.

1. In astrocytes derived from patients with sporadic and inherited AD , the authors found decreased mitochondria function, and as a result sugar processing was impaired. This was shown to be in line with early memory loss symptoms.
2. By increasing the amount of HK1, the authors found that it improved the function of mitochondria and sugar processing in astrocytes of individuals with sporadic, but not inherited AD. The results highlight differences between sporadic and inherited AD, suggesting that there are diverging pathways by which astrocytes use HK1 between the two groups.

What do the findings mean going forward for people with the disease?

This study highlights metabolic deficits in AD patient-derived astrocytes, and indicates the important role HK1 plays in energy production. The results suggest that HK1 could be a potential therapeutic target to restore sugar processing in sAD, which may influence memory and cognitive function.

This study can be found at
https://www.nature.com/articles/s41380-024-02746-8#citeas 

Paper title
Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer’s disease astrocytes

Lead author
Simon Bell and Heather Mortiboys

Publication details including date of publication
13th September 2024