Reducing brain cholesterol levels could protect the brain and block the effects of the disease, a new study suggests.
- Alzheimer’s disease can cause a specific form of cholesterol to build up in the brain.
- In a trial on mice, a treatment made it possible to reduce the level of this cholesterol and limit brain damage linked to Alzheimer’s.
- The mice were able to retain their ability to perform basic tasks.
More than 35 million people suffer from Alzheimer’s disease, according to figures from the Alzheimer Research Foundation. Today, the treatments available only make it possible to slow the progression of the neurodegenerative pathology. But recent scientific work brings hope for new drugs capable of blocking this dementia. In the magazine Neuronresearchers from the Washington University School of Medicine present their findings: they concern a form of brain cholesterol associated with Alzheimer’s.
Alzheimer’s disease: links between cholesterol and brain damage
In Alzheimer’s disease, cognitive decline is caused by the overaccumulation of a brain protein called tau. “Wherever tau accumulates, nearby brain tissue begins to degenerate and die.”specify the authors in a communicated. However, in work on laboratory mice suffering from a form of Alzheimer’s disease, they found that these tau deposits lead to the accumulation of a form of cholesterol in the brain, known as cholesterol esters. According to their findings, reducing their levels helps prevent brain damage and behavioral changes in mice.
“The link between cholesterol and dementia is not as far-fetched as it seemsthey develop. The biggest genetic risk factor for Alzheimer’s disease is APOE, a gene involved in activating immune cells in the brain.” Defects in the activation of these cells cause damage to brain tissue. But APOE is also responsible for transporting cholesterol and other lipids in the blood.
Alzheimer’s: excess lipids with certain genetic variants
To better understand the links between APOE and brain damage, the authors studied mice with a strong genetic predisposition to the accumulation of the tau protein. American scientists also genetically modified rodents: they replaced their APOE gene with a variant present in humans, APOE3, which is associated with an average risk of Alzheimer’s disease or by APOE4, which doubles or even triples the risk. In some mice, no modification was made.
“The investigation found that APOE4 is linked to distorted lipid metabolism in the brain, observe the authors. In 9.5-month-old mice carrying APOE4, the same brain areas that were atrophied and damaged also accumulated excess lipids. Microglia, immune cells, were filled with cholesterol esters. “Lipid-filled microglia become hyperinflammatory and start secreting things that aren’t good for the brain“, explains David M. Holtzman, lead author of the study.
Alzheimer’s: a treatment lowering lipid levels seems effective
Scientists then hypothesized that removing lipids could potentially reduce brain inflammation and neurodegeneration. In a second trial, they administered a drug targeting the LXR (liver X receptors) which lowers lipid levels in cells, to mice with a genetic predisposition to tau protein and carrying APOE4. In untreated animals, brain damage is very significant after 9 months: they can no longer perform basic tasks, such as building a nest.
On the other hand, “lMice given the drug retained more brain volume than those given a placeboobserve the authors. They also had lower tau levels, fewer inflammatory cells and inflammation, less loss of synapses in their brains, and were better at building nests..” In short, this treatment helped reduce the effects of Alzheimer’s disease on the brain.
Neurodegenerative diseases: towards a possible treatment?
“What’s exciting is that we see all of these effects in an animal model that shares many features with human neurodegenerative diseasesrejoices David M. Holtzman. This type of approach could be very promising.”
For now, the scientific community must overcome an obstacle: the treatment has effects on the metabolism of lipids in the liver and can lead to hepatic steatosis.
If researchers succeed, the drug could have beneficial effects not only on neurodegenerative pathologies but also on heart diseases. “There are many similarities between the mechanism that drives immune cells to damage the brain in Alzheimer’s disease and that which drives the same types of immune cells to cause vascular damage in atherosclerosis.”, adds David M. Holtzman. “In both cases, lipids accumulate in immune cells, making them hyperinflammatory and damaging nearby tissues. Getting rid of this lipid buildup can have a dual effect for human health.”