Studies by researchers at Washington University School of Medicine in St. Louis have found that high levels of a normal protein that is associated with reduced heart disease also protects against Alzheimer’s-like brain damage in mice. The study results suggest that raising levels of the low-density lipoprotein receptor (LDLR) could potentially help to slow or stop cognitive decline.
“There are not yet clearly effective therapies to preserve cognitive function in people with Alzheimer’s disease,” said David Holtzman, MD, the Andrew B. and Gretchen P. Jones professor and head of the department of neurology. “We found that increasing LDL receptor in the brain strongly decreases neurodegeneration and protects against brain injury in mice. If you could increase LDL receptor in the brain with a small molecule or other approach, it could be a very attractive treatment strategy.”
Holtzman is senior author of the team’s published paper in Neuron, which is titled, “Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms.”
By the time people with Alzheimer’s disease start exhibiting memory and cognitive difficulties, the disease has may already have been developing in their brains for two decades or more, and there will be substantial damage to brain tissue. As the disease progresses, the damage continues to accumulate and symptoms worsen. During the long, slow development of Alzheimer’s disease, plaques of amyloid protein gradually accumulate in the brain. After many years, another brain protein, called tau, starts forming tangles that become detectable just before Alzheimer’s symptoms arise. The tangles are thought to be toxic to neurons, and their spread through the brain is a precursor to the death of brain tissue and cognitive decline.
Apolipoprotein E (ApoE) is a lipid-binding protein that carries lipids and cholesterol for their transport and metabolism. APOE is linked to both cholesterol metabolism and Alzheimer’s disease. High cholesterol in the blood is associated with increased risk of Alzheimer’s disease, although the exact nature of the association is unclear.
In humans there are three major APOE alleles: APOE2, APOE3, and APOE4. APOE4 strongly increases the risk of developing late-onset Alzheimer’s disease (AD), whereas APOE2 reduces AD risk relative to APOE3. In fact, the authors wrote, “APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE also strongly regulates brain ß-amyloid (Aß) deposition, in a dose- and isoform-dependent manner (E4 > E3 > E3), the investigators further pointed out.
Holtzman, and first author Yang Shi, PhD, a postdoctoral researcher, had previously shown that APOE drives tau-mediated degeneration in the brain by activating microglia, the brain’s cellular janitorial crew. Once activated, microglia can injure neural tissue in their zeal to clean up molecular debris. However, the researchers acknowledged, “ … how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear.” Researchers have also shown that LDLR is one of the two primary metabolic receptors (the other is LDLR-related protein 1, LRP1) mediating clearance of apoE lipoproteins.
For their reported studies, Shi, Holtzman, and colleagues including co-senior author Jason Ulrich, PhD, an associate professor of neurology, studied mice that were predisposed to develop Alzheimer’s-like neurodegeneration because they had been genetically modified to develop tau buildup in the brain, much like people with Alzheimer’s disease and other forms of dementia. The researchers bred these tau mice (P301S transgenic animals) with mice genetically modified to overexpress LDL receptor (LDLR OX) in their brains. The resulting offspring had high levels of LDL receptor and a propensity to develop Alzheimer’s-like brain damage by the time they were nine months old, which is similar to middle age in a person.
Higher levels of LDL receptor limit the damage APOE can do in part by binding to APOE and degrading it. Higher levels of LDL receptor in the brain, therefore, should pull more APOE out of the fluid surrounding brain cells and mitigate damage even further, the researchers reasoned. They compared their four groups of mice: normal, control animals, tau mice, mice with high levels of LDL receptor, and tau mice with high levels of LDL receptor.
At nine months of age, the normal mice and those with high levels of LDL receptor had healthy looking brains. The tau mice had developed severe brain atrophy and neurological damage. But the tau mice with high levels of LDL receptor 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 toward a less damaging pattern of activation. “LDLR-overexpressing microglia downregulate Apoe and show suppressed activation,” the published paper states. “Here, we show that overexpressing an apoE metabolic receptor, LDLR, in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration, … we found that LDLR OX protects against tau pathology and tau-associated neurodegeneration, suggesting LDLR as a new therapeutic target for treating tauopathy.”
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 levels of LDL receptor in the liver and some other tissues. It is not known whether they affect LDL receptor levels in the brain.
Holtzman commented, “Alzheimer’s develops slowly through multiple phases, and the degeneration phase when tau is building up is when the symptoms arise and worsen. In terms of 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 receptor in other ways.”