Astrocyte study identifies new therapeutic target for Alzheimer’s disease

At least 50 million people worldwide suffer from some form of dementia. Alzheimer’s disease is the most common form of dementia. It is a progressive and irreversible neurodegenerative disease that primarily affects memory and cognitive function. Symptoms include memory loss that interferes with daily life, poor judgment, and difficulty performing normal daily tasks. There is currently no cure.

The most common form of Alzheimer’s disease is called sporadic Alzheimer’s disease, which appears due to a complex combination of genes, environment and lifestyle. It has no specific family link.

Astrocytes are an important cell subtype that make up the majority of cells in the nervous system. They perform many functions, including providing nutrients, support, and insulation to neurons. In early Alzheimer’s disease, astrocytes have been shown to have metabolic problems and are not able to process information properly, impacting the energy used to help neurons function efficiently.

“Most people focus on neurons, but there are actually more astrocytes in the brain than neurons. Once the metabolism of the astrocytes is disrupted, the astrocyte will certainly not be able to provide as much support to the neurons,” says Professor Heather Mortiboys of the Neuroscience Institute.

A study led by Dr Simon Bell from the University of Sheffield’s Institute of Neuroscience was the first to identify the impact of damaged astrocytes in sporadic Alzheimer’s disease on the cellular powerhouses known as mitochondria. The study found that damaged astrocytes in Alzheimer’s disease produce less energy and put more stress on the mitochondria.

The work is published in the journal Molecular psychiatry.

The study found that a key enzyme called hexokinase 1 (HK1) was lower in astrocytes from people with sporadic Alzheimer’s disease. The study found that increasing this enzyme could improve the energy of astrocytes with sporadic Alzheimer’s disease and reduce the negative impact of abnormal astrocytes.

The study was led by Dr Simon Bell and directed by Professor Mortiboys. Many researchers were involved in the study, including Hollie Wareing, Francesco Capriglia, Rachel Hughes, Katy Barnes, Alexander Hamshaw, Dr Liam Adair, Allan Shaw, Alicja Olejnik, Suman De, Elizabeth New, Professor Dame Pamela J. Shaw, Dr Matteo De Marco, Professor Annalena Venneri, Dr Daniel J. Blackburn and Laura Ferraiuolo.

“For this study, we took samples from patients with sporadic Alzheimer’s disease through skin biopsies and grew skin cells, or fibroblasts, in the laboratory. We then used reprogramming techniques to turn them into stem cells and differentiate them into astrocytes,” explains Professor Mortiboys.

“When comparing astrocytes between sporadic and familial Alzheimer’s disease, we found key changes in the mitochondria. In addition to having a different shape and size, there are also changes in the glycolytic pathways, meaning that the astrocytes have an overall energy deficit. The study highlights the different mechanisms at play between sporadic and familial Alzheimer’s disease and how boosting the HK1 protein could improve cellular metabolism in early Alzheimer’s disease,” she adds.

Research suggests that problems in astrocyte metabolism may occur early in Alzheimer’s disease and highlights the potential role of HK1 in these processes.