High-density lipoprotein (HDL) is often referred to as "good" cholesterol because it transports fat molecules out of blood vessels, protecting against stroke and heart disease. Now, researchers at Weill Cornell Medical College have discovered that HDL in blood also carries a protein that powerfully regulates immune function. Together they play an important role in preventing inflammation in the body.

In the study, published June 8 in Nature, the investigators found that a lipid molecule called sphingosine 1-phosphate (S1P) that is bound to HDL suppresses the formation of T and B immune cells in the bone marrow. In doing so, HDL and S1P block these cells from launching an abnormal immune response that leads to damaging inflammation, a hallmark of many disorders including autoimmune diseases, cardiovascular disease and neuroinflammatory disease, such as multiple sclerosis.

"Our study shows that S1P that is bound to HDL helps prevent inflammation in many tissues," said senior investigator Dr. Timothy Hla, director of the Center for Vascular Biology and a professor of pathology and laboratory medicine at Weill Cornell. "When there is less S1P that is bound to HDL in blood, there are more B and T cells that can be activated to produce unwanted inflammation."

Dr. Hla has been studying S1P for more than two decades. He discovered that it is a key regulator of vascular function, and that about 65 percent of S1P in blood is bound to apolipoprotein M (ApoM), a member of the lipoprotein family, within the HDL particle. But until this study, the researchers did not know what specific function HDL-bound S1P served.

The team, including first author Dr. Victoria Blaho, an instructor in pathology and laboratory medicine, and researchers from the National Institutes of Health and Stanford University, studied mice that lacked HDL-bound S1P.

Dr. Timothy Hla. Photo credit: Carlos Rene Perez

Mice lacking HDL-bound S1P developed worse inflammation in a model of multiple sclerosis. The reason for this, the investigators found, is that HDL-bound S1P suppresses the formation of T and B immune cells in the bone marrow. While both immune cells help fight infection, an overabundance of these cells can also trigger unwanted inflammation.

The findings help explain why blood HDL levels are such an important measure of cardiovascular health, Dr. Hla said.

"Blood HDL levels are associated with heart and brain health — the higher the HDL in blood, the less risk one has for cardiovascular diseases, stroke, and dementia," Dr. Hla said. "The corollary is that the lower the HDL, the higher the risk of these diseases." Blood levels of ApoM and S1P have not been studied in these diseases.

The findings further suggest that molecules that mimic HDL-bound S1P could be useful in reducing damaging inflammation that has gone awry, Dr. Hla said. Such molecules are not known and will need to be developed in the future.

However, a related S1P1 receptor inhibitor called Gilenya, has already been approved for use in multiple sclerosis, a condition in which the immune system attacks nerve fibers due to unwanted inflammation, Dr. Hla said.

"The unique function of HDL-S1P could be further exploited for innovative therapeutic opportunities," he said.

For this research, Dr. Blaho received funding from the National Institutes of Health (F32 CA14211), the New York Stem Cell Foundation (C026878) and the Leon Levy Foundation (supported through the Feil Family Brain and Mind Research Institute). Dr. Hla received funding from the NIH (HL67330 and HL89934), as well as through Fondation Leducq.

Memory loss in older adults often raises the scary specter of Alzheimer's disease — even if the dragging memory is just routine aging. And if Alzheimer's is diagnosed, patients have no idea what to expect, and when.

This image shows how the baseline pattern of atrophy (top panel) in a patient with Alzheimer’s Disease can be extrapolated to 5 years (middle) and 10 years out (bottom). Image credit: Eve LoCastro and Ashish Raj, IDEAL Laboratory, Weill Cornell Medical College

But this big gap in clinical practice surrounding dementia may soon be closed. A research team at Weill Cornell Medical College and the University of California, San Francisco has developed a mathematical model that determines where in the brain Alzheimer's has spread, predicts where it will appear next and how fast the brain's atrophy patterns will change — giving patients a roadmap of their future.

It can also tell when mild cognitive impairment (MCI) — often believed to be a precursor to Alzheimer's — is just simple memory loss, without further progressing to the Alzheimer phase.

The model, published Jan. 15 in the journal Cell Reports, is based on the new understanding that the two toxic proteins that are the hallmarks of Alzheimer's — tau and amyloid beta — spread in a neuron-to-neuron, prion-like fashion from the hippocampus, where the disease develops, to networks of neurons throughout the brain in a very predictable way.

"Neurologists today cannot tell a person with any certainty what a person with MCI or Alzheimer's is going to experience in the future," said lead author Dr. Ashish Raj, an associate professor of computer science in radiology at Weill Cornell. "This is a very debilitating problem if you are the person who is undergoing early signs of dementia and you want to know what will happen to you and when.

"With our model, we know exactly where Alzheimer's will go, how fast it will go and which parts of the brain it will affect," added Dr. Raj, who is also an associate professor of neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell. "Because of this, we might be able to say with some confidence the time frame in which a person will convert to dementia or whether they will convert to dementia at all. This is very unique — and long needed."

The team studied the brains of 418 living participants with diagnoses of Alzheimer's or MCI, using a MRI brain atrophy scan and PET glucose metabolism scan, a test that looks at activity in the brain. Together, the scans provide a spatial map of brain atrophy in individual patients.

Dr. Raj expects that roadmaps of many neurodegenerative diseases, such as Parkinson's, will soon be possible. He says the maps will be based on the new understanding that all types of dementia is caused by toxic proteins that spread from one neuron to the next one, in distinct patterns.

"We have long known that neurodegeneration is linked to one group of toxic proteins or another, but the discovery that these proteins spread, in a prion-like pattern, is relatively new," Dr. Raj said. "That tells us that the trajectory of the neurodegenerative disease is purely a deterministic process — one that we can now use to inform our clinicians and patients."

For many years, scientists have known that degeneration of neurons — nerve cells that transmit signals to and from the brain — caused Alzheimer's dementia, an incurable disease afflicting more than 35 million people worldwide and approaching epidemic proportions. Now, a new study from Weill Cornell Medical College reveals that changes occurring in blood vessels also play a major role — by limiting the supply of oxygen and glucose to the brain and contributing to the neuronal damage causing the disease.

Amyloid-beta — a protein fragment that accumulates in the brains of Alzheimer's patients — alters the normal function of neurons and sets the stage for dementia to develop. At the same time, it also acts directly on endothelial cells, the cells lining blood vessels that control the delivery of oxygen and glucose to the brain, thereby damaging their DNA, or genetic makeup, according to the study published Oct. 29 in Nature Communications.

Certain repair processes are put in place to override the damage, including activation of the DNA repair enzyme poly(ADP)-ribose polymerase, which ends up producing large amounts of the chemical ADP-ribose. ADP-ribose, in turn, activates a cellular surface channel — known as transient receptor potential melastatin-2 (TRPM2) — unleashing a flood of calcium ions into the endothelial cells. This sudden and massive calcium overload cripples the endothelial cells and disrupts the supply of blood to the brain, resulting in insufficient delivery of vital oxygen and glucose to the working brain cells.

"The brain blood vessels become unable to supply the oxygen and nutrients needed to fuel the most energy-demanding brain functions, such as learning and memory," says the senior author of the study, Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology.

The research, conducted in mice, identified a mechanism by which this amyloid-beta peptide impedes the regulation of blood flow to the brain. It also highlighted TRPM2 channels as a potential therapeutic target to counteract cerebrovascular dysfunction in Alzheimer's dementia and related conditions. Drugs are being developed that act on this channel to rescue the dysfunction of endothelial cells, enhance blood-flow delivery to the energy-deprived brain and delay disease progression.

Controlling hypertension, diabetes and obesity — so-called vascular risk factors — also may retard the progression and reduce the risk of Alzheimer's dementia, Dr. Iadecola says. Studies in which patients have been carefully monitored for decades have revealed that people who have these vascular risk factors in their 50s and 60s have an increased risk of developing Alzheimer's later in life.

About half of patients with an Alzheimer's diagnosis also have brain damage resulting from insufficient blood flow, indicating that the blood vessel alterations that contribute to stroke also could accelerate Alzheimer's decline, Dr. Iadecola says. Autopsy studies have confirmed that stroke and Alzheimer's pathologies often coexist in the same brain.

"No one knows why exactly," Dr. Iadecola says. "But most likely, as you get older, especially if vascular risk factors are present, you also tend to have more damage to your blood vessels, which favors accumulation of amyloid beta in the brain. In turn, amyloid beta causes even more damage to blood vessels and further reduces their ability to nourish the brain. It's a vicious cycle that eventually harms brain centers involved in learning and memory and leads to dementia; drugs inhibiting TRPM2 may break this cycle and help reduce the amyloid burden in the brain."

The paper was first authored jointly by Drs. Laibaik Park, assistant professor, and Gang Wang, associate research professor, both in the Feil Family Brain and Mind Research Institute.