Longevity Briefs: How Does Obesity Promote Alzheimer’s Disease?

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Alzheimer’s disease is the most common form of dementia, affecting millions of people worldwide. Despite extensive research, the exact mechanisms behind AD remain elusive, and the condition is incurable, so every effort must be made to prevent it in the first place. Recent studies have suggested a link between obesity and the development of AD. However, the molecular mechanisms connecting obesity and AD are not fully understood. This research investigates the possibility that lipids (fats) themselves may promote AD through their direct effects on microglial cells within the brain. Described as the ‘janitors’ of the brain, microglia support the function of other brain cells, helping to repair damage and clear up debris including amyloid beta, a protein thought to contribute to AD development.

The discovery:

Researchers found that when BV2 microglial cells were exposed to lipids in order to simulate a high-fat environment, they tended to become senescent. Senescence is a state in which cells are unable to divide or function properly, and senescence in microglia appears to be associated with brain ageing and dementia. The microglia also produced more of a protein called ANGPTL4. This is a type of molecule called an adipokine, which is mainly released by fat cells to control things like fat storage and appetite. Higher levels of ANGPTL4 are associated with both obesity and AD. Similar results were obtained in mice, with animals fed a high fat diet having increased levels of ANGPTL4.

The researchers then tried using genetic manipulation to increase the production of ANGPTL4 in microglia, and found that this was associated with impaired microglial function. These microglia once again showed signs of senescence and reduced anti-inflammatory activity, suggesting that ANGPTL4 can cause microglia to stop functioning properly.

Finally the researchers analysed data from the UK biobank, an anonymous health and lifestyle database. Studying a sample of 51,662 participants in total, they found that those with Alzehimer’s disease had significantly higher levels of ANGPTL4 in their blood compared to healthy participants. In a smaller more detailed blood analysis of just 12 people, AD patients had higher ANGPTL4 levels than healthy participants even when there was no difference in BMI between the two groups. Looking only at the 668 participants who did have AD, they found that those with higher BMI had significantly higher ANGPTL4 levels.

Expression of ANGPTL4 in healthy people vs AD patients (left) and in AD patients with different BMI ranges (right).
*ANGPTL4-mediated microglial lipid droplet accumulation: Bridging Alzheimer’s disease and obesity*

The implications:

This study suggests that ANGPTL4 in microglia may be an important link between obesity, cognitive ageing and Alzheimer’s disease. Both high levels of fat and artificially increased ANGPTL4 gene expression caused microglia to become dysfunctional, and ANGPTL4 levels were elevated among patients with AD and with higher BMI.

These mechanisms will need to be studied in more detail, as there are still many complexities to unravel. Unsaturated fatty acids are considered to protect the brain against neurodegenerative diseases, so it is not simply a case of more dietary fat being bad. There may also be some reverse causation, as it has been suggested that AD might increase the risk of developing obesity.