Lay summary by Hollie Wareing, reviewed by Dr Scott Allen and a Dementia Lay Panel
Background
As we age, our brains shrink and our thinking becomes slower. In Alzheimer’s Disease (AD) the changes are different and not part of normal ageing. AD is marked by the build-up of two proteins, Amyloid-β and Tau, affecting the cells within the brain. One of the first brain cells affected are neurones, essential for processing and transmitting information. During AD, this function is disrupted, and overtime this decreases memory and thinking ability interfering with everyday life.
A different type of brain cell, microglia, support and protect neighbouring neurones to maintain a healthy environment. One change observed in microglia during AD is the increased number of lipid-droplets found inside them. Lipid-droplets are particles that act as storage containers for fats (lipids) and play an important role in cell function. Although microglia lipid-droplets are found in the aged brain, it is not well understood how the increased number contributes to the risk of AD.
Why is the study important?
One risk for developing AD is our genes (traits) containing instructions to tell cells how to carry out specific functions. A gene called APOE has been identified as a risk factor for AD. The APOE gene provides instructions to make the APOE protein which is involved in the breakdown and storage of fats in brain cells, particularly microglia.
The APOE gene has several different types with the most common called APOE/2, APOE/3, and APOE/4. The different forms result in slightly different versions of the APOE protein, which affects its function. However, it remains unclear if APOE is associated with the formation and regulation of microglia lipid-droplets. This study therefore increases the knowledge of APOE lipid-droplet association.
What did the authors do and how did they do it?
By using post-mortem brain tissues of AD patients, individuals were split into three groups based on their APOE status; APOE/4 gene (AD diagnosed), APOE/3 gene (AD diagnosed), and not AD diagnosed (Controls). The authors looked at the amount of microglia and lipid-droplets in the brain tissue using a dye (oil red) that stains for lipid-droplets.
Next, the authors investigated if the APOE/4 trait contributes to the formation of lipid-droplets in microglia by using live cell imaging to visualise the lipid-droplets. Finally, lipid-droplets from the microglia were added to neurones to test if they cause toxic effects in a different brain cell. The neurones were stained with a dye (AT8), a dye to detect Tau, a marker of AD harmfulness.
What are the results?
The authors found that the microglia expressed ACSL1, a molecule that is involved in lipid-droplet formation and function. The amount of ACSL1 was higher in AD microglia than in non-AD microglia, and AP0E/4 was more than AP0E/3. These results suggest that ACSL1 may be an important molecule for the formation and function of lipid-droplets. To conform this, the authors looked at the amount of oil red+ lipid-droplets.
The oil red+ lipid-droplets were higher in AD microglia than non-AD microglia, and APOE/4 was more than APOE/3. This correlated with the number of ACSL1 microglia, indicating that ACSL1 may be an important in lipid-droplet formation and function. The results also indicate that the different APOE genes may also have gene dependent roles in the regulation of lipid-droplet levels. Finally, when lipid-droplets were added to neurones this increased Tau levels and harmfulness the most in the AP0E/4 compared to AP0E/3 and controls. The authors concluded that APOE4/4 microglia have more lipid-droplet harmfulness than that of APOE3/3 and controls due to the increased level of Tau, a protein which affects the brain cells in AD.
What do the findings mean going forward for people with the disease?
The study suggests a connection between genetic risk factors for AD with microglial lipid-droplet build up and toxicity. Highlighting the importance of lipid-droplets in both normal and AD brain cells. This opens the opportunity to investigate therapeutic strategies for AD targeting lipid-droplets.
This study can be found at
APOE4/4 is linked to damaging lipid-droplets in Alzheimer’s disease microglia | Nature
Paper title
APOE4/4 is linked to damaging lipid-droplets in Alzheimer’s disease microglia.
Lead Authors
Michael S. Haney and Tony Wyss-Coray
Publication details including date of publication
13th March 2024