All cells, especially brain cells, need lipids to survive. Special transport particles – known as lipoproteins – are required to move water-insoluble lipids through the body. Each lipoprotein contains apolipoproteins, a group of molecules onto which lipids can be loaded. The most well-known of these are LDLs and HDLs, which perform a kind of pickup and delivery service for the lipid cholesterol.
The brain’s neurons need lipids in order, for example, to form synapses – junctions – between each other. The fat molecules are produced by astrocytes in the brain, whose name is derived from their star shape. Apolipoprotein E, or ApoE, which serves as the transport protein, comes in three variants in humans, two of which – ApoE3 and ApoE4 – are more common.
ApoE is the strongest genetic risk factor for Alzheimer’s dementia
Scientists have known for some time that the gene containing instructions for making ApoE4, a variant found in about 15 percent of people, significantly increases the risk of developing Alzheimer’s dementia. “People with two ApoE4 genes have a twelve times higher risk compared to those with two ApoE3 genes,” says Professor Thomas Willnow, who heads a lab at Berlin’s Max Delbrück Center for Molecular Medicine (MDC) that focuses on molecular cardiovascular research. “Statistically speaking, it is almost certain that an 85-year-old with two ApoE4 genes will contract Alzheimer’s.”
Why people with the ApoE3 variant are much better protected against age-related dementia is the central question that Willnow is currently seeking to answer. The MDC scientist has now been awarded an €80,000 grant from the non-profit Alzheimer Forschung Initiative (AFI).
The organization has since 1995 been raising private funds to achieve it primary aim – to one day find a cure for Alzheimer’s. The public ambassador for the AIF, the largest private supporter of Alzheimer’s research at German universities and public institutes, is the TV presenter Okka Gundel, whose grandmother died of Alzheimer’s.
A receptor found on neurons plays a crucial role
The MDC scientist Willnow is considered an expert in the field of ApoE research. In experiments on mice, he has discovered, for example, that ApoE3 can only develop its protective function if the animals carry an additional receptor called sortilin in their neuronal membranes. What this receptor does is help shuttle the lipids transported by ApoE into the neurons.
“We were able to show that mice with a human ApoE4 variant in their brain consistently have large amounts of a protein called amyloid-beta, or A beta,” says Willnow. “And this is even true when an animal’s sortilin receptor isn’t functioning as it should.” A higher level of A beta leads to the build-up of plaques in the brain – a hallmark of Alzheimer’s – and is thus associated with a higher risk of developing the disease.
The mice carrying the human ApoE3 gene, however, were found to have only small quantities of A beta – provided that the rodents’ sortilin receptor was intact. When Willnow and his team switched off the sortilin gene, subsequent tests showed that there was a high level of A beta in the mice’s brains despite the presence of the usually protective ApoE3 variant.
The aim is to better understand lipid metabolism in the brain
“We are now studying four different mouse models,” explains Willnow. “The first group of mice is engineered with ApoE3 and sortilin, the second group with ApoE3 but no sortilin, the third group with ApoE4 and sortilin, and the fourth group with ApoE4 but no sortilin.” Willnow now plans to use the funding from the AFI to study how the lipid metabolism in the brain of these mice differs and what neurodegenerative effects this has on the rodents.
“My hope is that we find a special lipid in the mice with ApoE3 and sortilin, one that possibly protects against the accumulation of A beta in the brain,” says Willnow.
“At some point it might be possible to boost the production of this lipid in carriers of the harmful ApoE4 variant or to directly administer the molecule to them – thereby reducing the risk of developing Alzheimer’s dementia.
High levels of sortilin protect against cardiovascular disorders
Sortilin is not only present in the brain. “We know, for example, that people with high levels of sortilin in their body are better protected against high cholesterol and thus against diseases that involve the heart or blood vessels,” says Willnow. Further research into this receptor may lead to treatments that not only help get a better handle on Alzheimer’s, but also on another major widespread disease – cardiovascular disease.