By the time people with Alzheimer’s disease begin to have difficulty remembering and thinking, the disease has been developing in their brains for two decades or more, and their brain tissue has already been damaged. As the disease progresses, the damage accumulates and their symptoms worsen.
Researchers at the Washington University School of Medicine in St. Louis have found that high levels of a normal protein associated with reduced heart disease also protect against Alzheimer’s-like brain damage – at least in mice. The results, published on June 21 in Neuron, suggest that increasing levels of the protein – known as the low-density lipoprotein receptor (LDL receptor) – could potentially be a way to slow or stop cognitive decline.
The discovery of the LDL receptor as a potential therapeutic target for dementia is surprising since the protein is much better known for its role in cholesterol metabolism. Statins and PCSK9 inhibitors, two groups of drugs widely prescribed for cardiovascular disease, work in part by increasing the levels of LDL receptors in the liver and certain other tissues. It is not known whether they affect the levels of LDL receptors in the brain.
There are as yet no clearly effective therapies for preserving cognitive function in people with Alzheimer’s disease. We found that increasing the LDL receptor in the brain greatly decreases neurodegeneration and protects against brain damage in mice. If you could increase the LDL receptor in the brain with a small molecule or some other approach, that could be a very attractive treatment strategy. “
David Holtzman, MD, senior author, Professor Andrew B. and Gretchen P. Jones and Head of Department of Neurology
The key to the importance of the LDL receptor lies in a different protein, APOE, which is also linked to both cholesterol metabolism and Alzheimer’s disease. High blood cholesterol is associated with an increased risk of Alzheimer’s disease, although the exact nature of the association is unclear.
During the long, slow development of Alzheimer’s disease, plaques of a protein called amyloid gradually build up in the brain. After many years, another protein in the brain called tau begins to form tangles that become detectable just before symptoms of Alzheimer’s disease appear. The tangles are believed to be toxic to neurons, and their spread throughout the brain predicts brain tissue death and cognitive decline. The first author, Yang Shi, PhD, postdoctoral researcher, and Holtzman previously showed that APOE causes tau-mediated degeneration in the brain by activating microglia, the brain’s cell janitorial team. Once activated, the microglia can damage neural tissue in its zeal to clean up molecular debris.
Higher levels of LDL receptors limit the damage that APOE can cause in part by binding to and degrading APOE. Higher levels of LDL receptors in the brain should therefore extract more APOE from the fluid surrounding brain cells and further attenuate the damage, the researchers said.
In this study, Shi, Holtzman and their colleagues, including co-lead author Jason Ulrich, PhD, associate professor of neurology, studied mice predisposed to developing Alzheimer-like neurodegeneration because they had been genetically modified. to develop a buildup of tau in the brain, just like people with Alzheimer’s disease and other forms of dementia. The researchers crossed the tau mice with mice genetically engineered to express high levels of LDL receptors in their brains. The resulting offspring had high levels of LDL receptors and a propensity to develop Alzheimer’s-like brain damage by the age of 9 months, which is similar to the average age in a person.
Next, the researchers compared the four groups: normal mice, tau mice, mice with high levels of LDL receptors, and tau mice with high levels of LDL receptors. At 9 months, normal mice and mice with high levels of LDL receptors had healthy-looking brains. The tau mice exhibited severe brain atrophy and neurological damage. In comparison, tau mice with high levels of LDL receptors were in much better shape. They had significantly less brain shrinkage and damage, their levels of certain forms of tau and APOE were significantly lower, and their microglia were shifted to a less damaging activation pattern.
“Alzheimer’s disease develops slowly in several phases, and the degenerative phase during which tau accumulates is when symptoms appear and worsen,” said Holtzman. “In terms of the quality of life for people with Alzheimer’s, this is a phase in which it would be great if we could intervene. I think this LDL receptor pathway is a good candidate because it has a strong effect, and we know it can be targeted in other parts of the body. This has motivated us over the last few years to try to develop programs to modulate the receiver in other ways. “
Washington University School of Medicine
Shi, Y., et al. (2021) Overexpression of the low-density lipoprotein receptor reduces neurodegeneration associated with tau compared to mechanisms related to apoE. Neuron. doi.org/10.1016/j.neuron.2021.05.034.