Massachusetts Institute of Technology School of Science

Higher Alzheimer’s Incidence in Women Linked to Modified Immune System Protein

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Scientists at Scripps Research and Massachusetts Institute of Technology (MIT) have found a clue to the molecular cause of Alzheimer’s disease (AD), which may also explain why women are at greater risk for the disease than men.

The team found that a particularly harmful, chemically modified form of an inflammatory immune protein called complement C3 was present at much higher levels in the brains of women who had died with AD, compared with the brains of men who had died with the disease. The results also showed that estrogen—levels of which drop during menopause—normally protects against the production of this form of complement C3.

“Our new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer’s, and may explain, at least in part, why the disease predominantly affects women,” said research lead Stuart Lipton, MD, PhD, professor and Step Family Foundation endowed chair in the department of molecular medicine at Scripps Research and a clinical neurologist in La Jolla, CA. Lipton is senior author of the team’s published paper in Science Advances, which is titled, “Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3.” In their paper the researchers concluded, “Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.” The study was a collaboration with a team led by Steven Tannenbaum, PhD, post-tenure Underwood-Prescott professor of biological engineering, chemistry, and toxicology at MIT.

AD, the most common form of dementia that occurs with aging, currently afflicts about six million people in the U.S. alone. “AD—characterized by the accumulation of misfolded amyloid-β (Aβ) peptide and neurofibrillary hyperphosphorylated tau tangles in the brain—is arguably the most common neurodegenerative disorder leading to dementia,” the team wrote.

Alzheimer’s disease is always ultimately fatal, usually within a decade of onset, and there is no approved treatment that can halt the disease process, let alone reverse it. The shortcomings of treatments reflect the fact that scientists have never fully understood how Alzheimer’s develops. “The etiology and pathogenesis of AD are incompletely understood, and effective, disease-modifying drug treatments are lacking,” they continued. Scientists also don’t know fully why women account for nearly two-thirds of cases. “Although tremendous strides have been made in AD research over the past decade, additional consideration of sex differences will be important to explain the increased incidence of disease in females.”

Lipton’s lab studies biochemical and molecular events that may underlie neurodegenerative diseases, including the chemical reaction that forms a modified type of complement C3—a process called protein S-nitrosylation (SNO). Lipton and his colleagues previously discovered this chemical reaction, which happens when a nitric oxide (NO)-related molecule binds tightly to a sulfur atom (S) on a particular amino acid building-block of proteins to form a modified SNO-protein.

Protein modifications by small clusters of atoms such as NO are common in cells and typically activate or deactivate a target protein’s functions. For technical reasons, S-nitrosylation has been more difficult to study than other protein modifications, but Lipton suspects that “SNO-storms” of these proteins could be a key contributor to Alzheimer’s and other neurodegenerative disorders. “SNO can influence protein activity, localization, conformation, or interactions with other proteins; aberrant protein SNO may play a key role in the pathogenesis of various neurodegenerative diseases,” the investigators commented in their paper. “Prior work has linked SNO proteins in neurons and glial cells to neurodegenerative diseases, including AD.”

For their newly reported study, the researchers used novel methods for detecting S-nitrosylation to quantify proteins modified in 40 postmortem human brains. Half of the brains were from people who had died of Alzheimer’s, and half were from people who hadn’t—and each group was divided equally between males and females.

In these brains, the scientists found 1,449 different proteins that had been S-nitrosylated. Among the proteins most often modified in this way, there were several that have already been tied to Alzheimer’s, including complement C3. Strikingly, the levels of S-nitrosylated C3 (SNO-C3) were more than six-fold higher in female Alzheimer’s brains compared to male Alzheimer’s brains. “Notably, SNO proteins associated with complement pathways are enriched in both male and female AD brains,” they stated. “However, SNO of C3, representing the point of convergence of the various complement cascades, was detected predominantly in female AD brains … In our SNO protein datasets, we observed a significant increase in SNO-C3 in female AD brains, exhibiting a 34.2-fold increase over female non-AD control brain.”

estrogen, Alzheimer's Disease, Women, S-nitrosylation Complement protein
In postmenopausal women, depletion of estrogen causes excessive elevation of nitric oxide (NO) in the brain and thus generates S-nitrosylated complement factor C3 (SNO-C3). SNO-C3 triggers activated microglial cells, the innate immune cells in the brain, to phagocytose (or “eat”) neuronal synapses—the connections that mediate signaling between nerve cells in the brain. This aberrant chemical biology process results in synapse loss, leading to cognitive decline in Alzheimer’s disease. [Chang-ki Oh and Stuart Lipton, Scripps Research]

The complement system is an evolutionarily older part of the human immune system. It consists of a family of proteins, including C3, that can activate one another to drive inflammation in what is called the “complement cascade.” Scientists have known for more than 30 years that Alzheimer’s brains have higher levels of complement proteins and other markers of inflammation, compared to neurologically normal brains. More recent research has shown specifically that complement proteins can trigger brain-resident immune cells called microglia to destroy synapses—the connection points through which neurons send signals to one another. Many researchers now suspect that this synapse-destroying mechanism at least partly underlies the Alzheimer’s disease process, and loss of synapses has been demonstrated to be a significant correlate of cognitive decline in Alzheimer’s brains.

Why would SNO-C3 be more common in female brains with Alzheimer’s? There has long been evidence that the female hormone estrogen can have brain-protective effects under some conditions; thus, the researchers hypothesized that estrogen specifically protects women’s brains from C3 S-nitrosylation—and this protection is lost when estrogen levels fall sharply with menopause.

“We hypothesized that menopause-associated up-regulation of inflammation in the brain could be causally linked to the aberrant increase in SNO-C3 that we observed,” the authors noted. “Experiments with cultured human brain cells supported this hypothesis, revealing that SNO-C3 increases as estrogen (β-estradiol) levels fall, due to the activation of an enzyme that makes NO in brain cells. This increase in SNO-C3 activates microglial destruction of synapses. “Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline,” they stated. “Thus, dysregulation of the complement system may play a role in the pathogenesis of AD and explain, at least in part, the female predominance of the disease.”

“Why women are more likely to get Alzheimer’s has long been a mystery, but I think our results represent an important piece of the puzzle that mechanistically explains the increased vulnerability of women as they age,” Lipton said. “To our knowledge, this is the first investigation comparing changes in NO-modified protein levels in the brains of male and female humans with AD,” the team stated. “ … our data suggest a unique mechanism by which protein SNO modulates complement (C3) activity in a sex-dependent manner, thereby providing a molecular link between NO signaling and the complement cascade in AD pathogenesis.”

The researchers now hope to conduct further experiments with de-nitrosylating compounds—which remove the SNO modification—to see if they can reduce pathology in animal models of Alzheimer’s and eventually in humans.

Seeing light in a new light.

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Scientists create never-before-seen form of matter

Harvard and MIT scientists are challenging the conventional wisdom about light, and they didn’t need to go to a galaxy far, far away to do it.

Working with colleagues at the Harvard-MIT Center for Ultracold Atoms, a group led by Harvard Professor of Physics Mikhail Lukin and MIT Professor of Physics Vladan Vuletic have managed to coax photons into binding together to form molecules – a state of matter that, until recently, had been purely theoretical. The work is described in a September 25 paper inNature.

The discovery, Lukin said, runs contrary to decades of accepted wisdom about the nature of light. Photons have long been described as massless particles which don’t interact with each other – shine two laser beams at each other, he said, and they simply pass through one another.

“Photonic molecules,” however, behave less like traditional lasers and more like something you might find in science fiction – the light saber.

“Most of the properties of light we know about originate from the fact that photons are massless, and that they do not interact with each other,” Lukin said. “What we have done is create a special type of medium in which photons interact with each other so strongly that they begin to act as though they have mass, and they bind together to form molecules. This type of photonic bound state has been discussed theoretically for quite a while, but until now it hadn’t been observed.

“It’s not an in-apt analogy to compare this to light sabers,” Lukin added. “When these photons interact with each other, they’re pushing against and deflect each other. The physics of what’s happening in these molecules is similar to what we see in the movies.”

To get the normally-massless photons to bind to each other, Lukin and colleagues, including Harvard post-doctoral fellow Ofer Fisterberg, former Harvard doctoral student Alexey Gorshkov and MIT graduate students Thibault Peyronel and Qiu Liang couldn’t rely on something like the Force – they instead turned to a set of more extreme conditions.

Researchers began by pumped rubidium atoms into a vacuum chamber, then used lasers to cool the cloud of atoms to just a few degrees above absolute zero. Using extremely weak laser pulses, they then fired single photons into the cloud of atoms.

As the photons enter the cloud of cold atoms, Lukin said, its energy excites atoms along its path, causing the photon to slow dramatically. As the photon moves through the cloud, that energy is handed off from atom to atom, and eventually exits the cloud with the photon.

“When the photon exits the medium, its identity is preserved,” Lukin said. “It’s the same effect we see with refraction of light in a water glass. The light enters the water, it hands off part of its energy to the medium, and inside it exists as light and matter coupled together, but when it exits, it’s still light. The process that takes place is the same it’s just a bit more extreme – the light is slowed considerably, and a lot more energy is given away than during refraction.”

When Lukin and colleagues fired two photons into the cloud, they were surprised to see them exit together, as a single molecule.

The reason they form the never-before-seen molecules?

An effect called a Rydberg blockade, Lukin said, which states that when an atom is excited, nearby atoms cannot be excited to the same degree. In practice, the effect means that as two photons enter the atomic cloud, the first excites an atom, but must move forward before the second photon can excite nearby atoms.

The result, he said, is that the two photons push and pull each other through the cloud as their energy is handed off from one atom to the next.

“It’s a photonic interaction that’s mediated by the atomic interaction,” Lukin said. “That makes these two photons behave like a molecule, and when they exit the medium they’re much more likely to do so together than as single photons.”

While the effect is unusual, it does have some practical applications as well.

“We do this for fun, and because we’re pushing the frontiers of science,” Lukin said. “But it feeds into the bigger picture of what we’re doing because photons remain the best possible means to carry quantum information. The handicap, though, has been that photons don’t interact with each other.”

To build a quantum computer, he explained, researchers need to build a system that can preserve quantum information, and process it using quantum logic operations. The challenge, however, is that quantum logic requires interactions between individual quanta so that quantum systems can be switched to perform information processing.

“What we demonstrate with this process allows us to do that,” Lukin said. “Before we make a useful, practical quantum switch or photonic logic gate we have to improve the performance, so it’s still at the proof-of-concept level, but this is an important step. The physical principles we’ve established here are important.”

The system could even be useful in classical computing, Lukin said, considering the power-dissipation challenges chip-makers now face. A number of companies – including IBM – have worked to develop systems that rely on optical routers that convert light signals into electrical signals, but those systems face their own hurdles.

Lukin also suggested that the system might one day even be used to create complex three-dimensional structures – such as crystals – wholly out of light.

“What it will be useful for we don’t know yet, but it’s a new state of matter, so we are hopeful that new applications may emerge as we continue to investigate these photonic molecules’ properties,” he said.