Published by
Stanford Medicine

Author

Chronic Disease, Immunology, Infectious Disease, Neuroscience, Research, Stanford News

ME/CFS/SEID: It goes by many aliases, but its blood-chemistry signature is a giveaway

ME/CFS/SEID: It goes by many aliases, but its blood-chemistry signature is a giveaway

signature

It’s the disease that dare not speak its name without tripping over one of its other names. Call it what you will – chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME) or its latest, Institute of Medicine-sanctioned designation, systemic exertion intolerance disease (SEID). It’s very real, affecting between 1 million and 4 million people in the United States alone, according to Stanford infectious-disease sleuth Jose Montoya, MD, who has closely followed more than 200 SEID patients for several years and done extensive testing on these patients in an effort to find out what’s causing their condition.

Different authorities have quoted different numbers regarding those with SEID. The name-calling and number-assigning squishiness stems from the fact that beyond its chief defining symptom – overwhelming, unremitting exhaustion lasting for six months or longer – it’s tough to pin down. Additional symptoms can range from joint and muscle pain, incapacitating headaches or food intolerance to sore throat, lymph-node enlargement, gastrointestinal problems, abnormal blood-pressure or hypersensitivity to light, noise or other sensations.

Research into the hows and whys of SEID has been plagued by the inability to establish any characteristic biochemical or neuroanatomical underpinnings of the disorder. Although many viral suspects have been interrogated, no accused microbial culprit has been indicted. To this day, there are no valid laboratory tests for diagnosing SEID.

But a burst of insight into SEID’s physiological substrate came only months ago when Stanford neuroradiologist Mike Zeineh, MD, PhD, working with patients from Montoya’s registry, found that they shared a pattern of white-matter loss in specific parts of the brain. The discovery drew a great deal of attention in the press as well as the CFS community. (See our news release about that study for details.)

Now a high-profile, multi-institution team including Montoya has published a study in Science Advances showing yet another physiological basis for a diagnosis of SEID: a characteristic pattern, or “signature,” consisting of elevated levels of various circulating immune-signaling substances in the blood.

Continue Reading »

Applied Biotechnology, Cancer, Evolution, Immunology, Research, Stanford News

Corrective braces adjust cell-surface molecules’ positions, fix defective activities within cells

Corrective braces adjust cell-surface molecules' positions, fix defective activities within cells

bracesStanford molecular and cellular physiologist and structural biologist Chris Garcia, PhD, and his fellow scientists have tweaked together a set of molecular tools that work like braces of varying lengths and torque to fix things several orders of magnitude too small to see with the naked eye.

Like faulty cell-surface receptors, for instance, whose aberrant signaling can cause all kinds of medical problems, including cancer.

Cell-surface receptors transmit naturally occurring signals from outside cells to the insides of cells. Molecular messengers circulating in the blood stumble on receptors for which they’re a good fit, bind to them, and accelerate or diminish particular internal activities of cells, allowing the body to adjust to the needs of the minute.

Things sometimes go wrong. One or another of the body’s various circulating molecular messengers (for example, regulatory proteins called cytokines) may be too abundant or scarce. Alternatively, a genetic mutation may render a particular receptor type overly sluggish, or too efficient. One such mutation causes receptors for erythropoietin – a cytokine that stimulates production of certain blood-cell types – to be in constant overdrive, resulting in myeloproliferative disorders. Existing drugs for this condition sometimes overshoot, bringing the generation of needed blood-cell types to a screeching halt.

Garcia’s team took advantage of the fact that many receptors – erythropoietin receptors, for example – don’t perform solo, but instead work in pairs. In a proof-of-principle study in Cell, Garcia and his colleagues made brace-like molecular tools composed of stitched-together antibody fragments (known in the trade as diabodies). They then showed that these “two-headed beasts” can selectively grab on to two members of a mutated receptor pair and force the amped-up erythropoietin receptors into positions just far enough apart from, and at just the right angles to, one another to slow down their hyperactive signaling and act like normal ones.

That’s a whole new kind of therapeutic approach. Call it “cellular orthopedics.”

Previously: Souped-up super-version of IL-2 offers promise in cancer treatment and Minuscule DNA ring tricks tumors into revealing their presence
Photo by Zoe

Applied Biotechnology, Bioengineering, Cancer, Genetics, Research, Stanford News

Minuscule DNA ring tricks tumors into revealing their presence

Minuscule DNA ring tricks tumors into revealing their presence

cool minicirclesAn animal study just published in Proceedings of the National Academy of Sciences shows how, in the not-distant future, doctors may be able to not only detect tumors early in humans, but also monitor the effectiveness of cancer drugs in real time, guide clinical trials of new drugs, and even screen entire populations of symptom-free people for nascent tumors that could have otherwise slipped under the radar.

The potential is huge. And the principal investigator, Sam Gambhir, MD, PhD, is credible: He chairs Stanford’s radiology department, directs the Canary Center at Stanford for Cancer Early Detection and has authored or co-authored nearly 600 peer-reviewed research publications.

From my news release about the study:

Imagine: You pop a pill into your mouth and swallow it. It dissolves, releasing tiny particles that are absorbed and cause only cancerous cells to secrete a specific protein into your bloodstream. Two days from now, a finger-prick blood sample will expose whether you’ve got cancer and even give a rough idea of its extent. That’s a highly futuristic concept. But its realization may be only years, not decades, away.

The key to early cancer detection lies in finding valid biomarkers: substances whose presence in a person’s blood or urine flags a probable tumor. (High blood levels of the molecule known as PSA, for example, can signify prostate cancer.) But although various tumor types indeed secrete characteristic substances into the blood, these same substances typically are made in healthy tissues, too, albeit usually in smaller amounts. So a positive test result for, say, PSA doesn’t necessarily mean the person has cancer. Contrariwise, a small tumor just may not secrete enough of the trademark substance to be detectable.

Gambhir’s team appears to have found a way to force any of numerous tumor types to produce a biomarker whose presence in the blood unambiguously signifies cancer, because no adult tissues – cancerous or otherwise – would normally be making it. This particular substance is a protein naturally present in human embryos as they’re forming and developing, but absent in adults.

The scientists designed a genetic construct, called a DNA minicircle, that contains a single gene coding for the telltale substance. DNA minicircles are tiny, artificial, single-stranded DNA rings about 4,000 nucleotides in circumference – roughly one-millionth as long as the strand that you’d get if you stretched the DNA in all 23 chromosomes of the human genome end to end.

Gambhir and his colleagues rigged their minicircles so that this sole gene would be “turned on” only inside cancer cells. (For more details on how to do this, please see my release.) They injected the minicircles into mice who had small tumors and mice who didn’t. Within 48 hours, a simple blood test indicated the presence of the biomarker in the blood of mice with tumors, but not in the blood of the tumor-free mice.The bigger the tumor volume, the more of the biomarker in the blood.

The technique will likely apply to a broad range of cancers, and can possibly be modified to help pinpoint budding tumors’ location in the body.

Previously: Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later, Nanoparticles home in on human tumors growing in mice’s brains, increase accuracy of surgical removal and Nanomedicine moves one step closer to reality
Photo by Jim Strommer

Imaging, Mental Health, Neuroscience, NIH, Research, Stanford News

Study: Major psychiatric disorders share common deficits in brain’s executive-function network

Study: Major psychiatric disorders share common deficits in brain's executive-function network

marble brainPsychiatric disorders, traditionally distinguished from one another based on symptoms, may in reality not be as discrete as we think.

In a huge meta-analysis just published in JAMA Psychiatry, Stanford neuroscientist and psychiatrist Amit Etkin, MD, PhD, and his colleagues pooled the results from 193 different studies. This allowed them to compare brain images from 7,381 patients diagnosed with any of six conditions – schizophrenia, bipolar disorder, major depression, addiction, obsessive-compulsive disorder, and a cluster of anxiety syndromes – to one another, as well as to brain images from 8,511 healthy patients.

Compared with healthy brains, patients in all six psychiatric categories showed a loss of gray matter in each of three separate brain structures. These three areas, along with others, tend to fire in synchrony and are known to participate in the brain’s so-called “executive-function network,” which is associated with high-level functions including planning, decision-making, task-switching, concentrating in the face of distractions, and damping counterproductive impulses.

The findings call into question a longstanding tendency to distinguish psychiatric disorders chiefly by their symptoms

(“Gray matter” refers to information-processing nerve-cell concentrations in the brain, as opposed to the “white matter” tracts that, like connecting cables, shuttle information from one part of the brain to another.)

As Etkin told me when I interviewed him for the news release we issued on this study, “these three structures can be viewed as the alarm system for the brain.” More from our release:

“They work together, signaling to other brain regions when reality deviates from expectations – that something important and unpredicted has happened, or something important has failed to happen.” That signaling guides future behavior in directions more likely to obtain desired results.

The studies of psychiatric patients that Etkin’s team employed all used a technique that yields high-resolution images of the brain’s component structures but can say nothing about how or when these structures work or interact with one another. However, that kind of imaging data was available for the healthy subjects. And, on analysis, those healthy peoples’ performance on classic tests of executive-function (such as  asking the test-taker to note the color of the word “blue,” displayed in a color other than blue, after seeing it briefly flashed on a screen) correlated strongly with the volume of gray matter in the three suspect brain areas, supporting the idea that the anatomical loss in psychiatric patients was physiologically meaningful.

The findings call into question a longstanding tendency to distinguish psychiatric disorders chiefly by their symptoms rather than their underlying brain pathology – and, by implication, suggest that disparate conditions may be amenable to some common remedy.

As National Institute of Mental Health Director Thomas Insel, MD, told me in an interview about the study, the Stanford investigators “have stepped back from the trees to look at the forest and see a pattern in that forest that wasn’t apparent when you just look at the trees.”

Previously: Hope for the globby thing inside our skulls, Brain study offers intriguing clues toward new therapies for psychiatric disorders and Study shows abnormalities in brains of anxiety-disorder patients
Photo by Philippe Put

Aging, Immunology, Neuroscience, Research, Stanford News, Stroke

Can immune cells’ anomalous presence in brain explain delayed post-stroke dementia?

Can immune cells' anomalous presence in brain explain delayed post-stroke dementia?

bees in the bonnetAbout every 40 seconds, someone in the United States has a stroke. About one in three of those people will eventually suffer from dementia if they live long enough, even if there’s been no initial damage to brain structures involved in memory and cognition. That’s a mystery.

In a recent study in The Journal of Neuroscience, Stanford neurologist and stroke expert Marion Buckwalter, MD, PhD, points a bony scientific finger at a major likely reason why having a stroke doubles a person’s risk of incurring dementia within the next decade.

The culprit, surprisingly, seems to be a type of normally very beneficial immune cells that under ordinary circumstances have no business being in the brain. These trespassers, called B cells, are best known for generating antibodies that fight off invading pathogens. As I wrote in my release on the new study:

The antibodies that B cells produce are normally of great value to us. They circulate throughout blood and lymph, and bind to microbial invaders, gumming up the pathogens’ nefarious schemes and marking them for destruction by other immune cells. Occasionally, B cells wrongly begin generating antibodies that bind to the body’s own healthy tissues, causing certain forms of autoimmune disease, such as rheumatoid arthritis. Rituxan, a drug approved by the Food and Drug Administration for this condition, is actually an antibody itself: Its target is a protein found on the surface of every B cell. Use of this drug depletes B cells in the body, relieving the symptoms of rheumatoid arthritis and other B-cell-mediated disorders.

The blood-brain barrier, which tightly controls what enters and what leaves the brain, can be disrupted by a stroke, permitting the anomalous appearance of B cells there. Buckwalter and her colleagues showed that in mice experiencing strokes, the affected brain region – immune-cell-free at least one week later – started filling up with B cells until, at seven and twelve weeks post-stroke, there were “tons” of them, she told me. Around the same time, these mice started showing signs of dementia that hadn’t been at all evident a mere week after the stroke.

But in mice of a strain that is genetically incapable of producing B cells, no such cognitive loss occurred. Not only that, but giving plain old ordinary mice Rituxan five days after a stroke prevented this post-stroke dementia.

Then Buckwalter and her team looked at preserved, autopsied brain-tissue samples from people who had had stroke and dementia. Once again, they observed inordinate numbers of B cells in the majority of these brains, suggesting that humans, too, can experience late but lasting infiltration of rampaging B cells into our brains after a stroke.

So maybe giving a Rituxan-like B-cell-depleting compound to these people within that first week after their stroke could stave off dementia.

This wouldn’t by advisable for all stroke patients. You don’t want to wipe out somebody’s B cells (usually, they’re good guys) unless they are causing trouble. And, as seen in the autopsied tissue samples, not all stroke sufferers’ brains fall into that category.

But, Buckingham noted, Rituxan or something like it could work a double shift as both a therapeutic and a diagnostic. Rituxan pretty much binds only to B cells (a prelude to killing them), so tagging the drug with an imaging agent that could be picked up by, say, an MRI scan might tell clinicians which stroke patients have, or don’t have, B’s in their bonnets.

Previously: Targeted stimulation of specific brains cells boosts stroke recovery in mice, Calling all pharmacologists: Stroke-recovery mechanism found, small molecule needed and Brain sponge: Stroke treatment may extend time to prevent brain damage
Photo by _annamo

Aging, Genetics, Immunology, Infectious Disease, Research, Stanford News

In human defenses against disease, environment beats heredity, study of twins shows

In human defenses against disease, environment beats heredity, study of twins shows

Pfc. Lane Higson and Pfc. Casey Higson, identical twins serving in Iraq with the Enhanced Combat Aviation Brigade, 1st Infantry Division. The twins, natives of Myrtle Beach, S.C., joined the Army together and have not separated since.I’m one of those people who’ve paid to have their genomes analyzed for the purpose of getting a handle on susceptibility to this or that disease as time goes by. So it was with great interest that I came across a new study of twins conducted by immunologist Mark Davis, PhD, and fellow Stanford investigators. The study, published in CELL, shows that our environment, more than our heredity, plays the starring role in determining the state of our immune system, the body’s primary defense against disease. This is especially true as we age.

Improving gene-sequencing technologies have focused attention on the role of genes in diseases. But the finding that the environment is an even greater factor in shaping our immune response should give pause to anyone who thinks a whole-genome test is going to predict the course of their health status over a lifetime.

“The idea in some circles has been that if you sequence someone’s genome, you can tell what diseases they’re going to have 50 years later,” Davis told me when I interviewed him for a news release I wrote on the study. But, he noted, the immune system has to be tremendously adaptable in order to cope with unpredictable episodes of infection, injury and tumor formation.

Davis, who heads Stanford’s Institute for Immunity, Transplantation and Infection, is worth taking seriously. He’s made a number of major contributions to the field of immunology over the last 30 years or so.  (Not long ago, I wrote an article about one of those exploits for Stanford Medicine.)

To find out whether the tremendous differences observed between different people’s immune systems reflec tunderlying genetic differences or something else, Davis and his colleagues compared members of twin pairs to one another. Identical twins inherit the same genome, while fraternal twin pairs are no more alike genetically than regular siblings, on average sharing 50 percent of their genes. (Little-known fun factoid: The percentage can vary from 0 to 100, in principle, depending on the roll of the chromosomal dice. But it typically hovers pretty close to 50 percent, just as rolling real dice gives you a preponderance of 6s, 7s, and 8s. Think of a Bell curve.)

Because both types of twins share the same in utero environment and, usually, pretty close to the same childhood environment as well, they make great subjects for contrasting hereditary versus environmental influence. (If members of identical-twin pairs are found to be no more alike than members of fraternal-twin pairs with respect to the presence of some trait, that trait is considered to lack any genetic influence.)

In all, the researchers recruited 78 identical-twin pairs and 27 pairs of fraternal twins and drew blood from both members of each twin pair. That blood was hustled over to Stanford’s Human Monitoring Center, which houses the latest immune-sleuthing technology under a single roof. There, the Stanford team applied sophisticated laboratory methods to the blood samples to measure more than 200 distinct immune-system cell types, substances and activities.

Said Davis: “We found that in most cases – including your reaction to a standard influenza vaccine and other types of immune responsiveness – there is little or no genetic influence at work, and most likely the environment and your exposure to innumerable microbes is the major driver.”

It makes sense. A healthy human immune system has to continually adapt to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more.

“The immune system has to think on its feet,” Davis said.

Previously: Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Immunology escapes from the mouse trap
Photo by DVIDSHUB

Imaging, Neuroscience, Research, Science, Stanford News

New insights into how the brain stays bright

New insights into how the brain stays bright

Neon brainAxel Brunger, PhD, professor and chair of Stanford’s Department of Molecular and Cellular Physioogy , and a team composed of several Stanford colleagues and UCSF scientists including Yifan Cheng, PhD, have moved neuroscience a step forward with a close-up inspection of a brain-wide nano-recycling operation.

A healthy adult brain accounts for about 2 percent of a healthy person’s weight, and it consumes about 20 percent of all the energy that person’s body uses. That’s a lot of sugar getting burned up in your head, and here’s why: Incessant chit-chat throughout the brain’s staggeringly complex circuitry. A single nerve cell (of the brain’s estimated 100 billion) may communicate directly with as many as a million others, with the median in the vicinity of 10,000.

To transmit signals to one another, nerve cells release specialized chemicals called neurotransmitters into small gaps called synapses that separate one nerve cell in a circuit from the next. The firing patterns of our synapses underwrite our consciousness, emotions and behavior. The simple act of tasting a doughnut requires millions of simultaneous and precise synaptic firing events throughout the brain and, in turn, precisely coordinated timing of neurotransmitter release.

You’d better believe these chemicals don’t just ooze out of nerve cells at random. Prior to their release, they’re sequestered within membrane-bound packets, or vesicles, inside the cells. Every time a nerve cell transmits a signal to the next one – which can be more than 100 times a second – hundreds of tiny chemical-packed vesicles approach the edge of the first nerve cell and fuse with its outer membrane, like a small bubble merging with a larger one surrounding it. At just the right time, numerous vesicles’ stored contents spill out into the synapse, to be quickly taken up by receptors dotting the nearby edge of the nerve cell on the synapse’s far side, where, like little electronic ones and zeroes in a computer circuit, they may either trigger or impede the firing of an impulse along that next nerve cell.

Each instance of bubble-like fusion – and this happens not only in neurotransmitter release but in hormone secretion and other processes throughout the body – is carefully managed by a complex of interconnecting proteins, collectively known as the SNARE complex. The molecular equivalent of a clamp, the SNARE complex guides the vesicle ever nearer to the nerve-cell’s surface and then, at just the right moment, squishes it up against the cell’s outer membrane. The vesicle bursts, spilling its contents into the synapse.

Myriad repetitions of this process typify the average day in the life of the average nerve cell. This requires not only a ton of energy (which I guess is where the doughnut comes in) but ultra-efficient recycling. The entire SNARE complex must be constantly disassembled, then reassembled. In a new study in Nature, Brunger and his associates snagged a set of near-atomic-scale snapshots of the SNARE complex as well as the molecular machinery that recycles its components, allowing them to make sophisticated guesses about how the whole thing works. (See the Howard Hughes Medical Institute’s news release on the study here.)

This has been a long time coming. In fact, Brunger’s lab first determined the molecular structure of the SNARE complex, via X-ray crystallography, in 1998. The careful decades-long process of tracking down the SNARE complex’s components and their interactions won Stanford neuroscientist Tom Sudhof, MD, the 2013 Nobel Prize in Medicine. But despite its immense importance, you probably haven’t heard much about it. Studies of molecular structures are in general opaque to lay readers, complicated systems such as the SNARE complex all the more so. The popular press pays attention to the awarding of the Nobel, but seldom to the long, towering staircase of incremental discoveries that was climbed to earn it.

Previously: Revealed: The likely role of Parkinson’s protein in the healthy brain, Step by step, Sudhof stalked the devil in the details, snagged a Nobel and But is it news? How the Nobel prize transformed “noteworthy” into “newsworthy”
Photo by Carolyn Speranza

Genetics, Research, Science, Stanford News

Show-off! Protein upstages DNA by ordering amino-acid add-ons

Show-off! Protein upstages DNA by ordering amino-acid add-ons

Show-offEvery living cell is a metropolis in which the vast bulk of work is performed by phenomenally productive laborers called proteins. Proteins work so hard – and the work that must be done in a cell changes so rapidly – that turnover in the labor force is immense. To maintain the brisk pace of life inside a cell, new proteins must constantly be assembled.

The machines responsible for that assembly are called ribosomes – as many as 10 million of them within a single mammalian cell, each capable of stapling together up to 200 amino acids (the building blocks of proteins) per second. The resulting amino-acid strings immediately fold themselves into characteristic structures reflecting their precise composition.

There are about 20 different varieties of amino acids, so the number of possible combinations a ribosome can make, in theory, is mind-boggling. But a ribosome doesn’t just piece together whatever protein suits its passing fancy. It carefully heeds instructions stored on lengthy strands of DNA inside the cell’s nucleus, in a massive library known as the genome: a gigantic set of genes (the recipes for proteins), written in a ribosome-readable chemical code. But genes never leave the nucleus, and ribosomes never enter it.

Bridging that physical gap is a substance called messenger RNA, chemically similar to DNA but physically far more flexible and athletic. Like couriers carrying copies of a royal edict, messenger RNA molecules constantly exit the nucleus, where they were produced as portable copies of one gene or another. They head for the watery suburbs of the cell where protein construction takes place. And there, they find a ribosome, climb in, are fed through the ribosome’s molecular machinery, and get spit out like spent ticker tape once the ribosome has finished reading the recipe and assembling the specified protein product.

Under ordinary circumstances, ribosomes faithfully follow genetic instructions. But with all that whirling and whirring, sometimes things go wrong: The mRNA molecule or the ribosome is defective or, for some other reason, the protein-in-the-making is faulty.

Misspelled or misfolded proteins can wreak havoc. Happily, cells have “quality control” teams that can pick apart poorly produced proteins, tear up malfunctioning messenger RNA and retire rotten ribosomes.

In exploring that process, Stanford biochemist Onn Brandman, PhD, and colleagues at the University of California and University of Utah may have turned molecular-biological dogma on its head. In a new study in Science, Brandman and his associates report that they’ve identified a member of the quality-control squad, a protein called rqc2, that gloms onto stalled ribosomes – and then does something no protein has ever previously been shown to do: call out for the delivery of two particular amino acids, which get attached in random sequences to the aberrant protein under construction.

“Our results defy textbook science, showing for the first time that the building blocks of a protein, amino acids, can be assembled without the standard blueprints,” Brandman told me. “In the case we observed, neither DNA nor messenger RNA but a protein directs that a pair of amino acids be randomly added, in small stretches, to the ends of proteins that have stalled mid-synthesis. The function of these ‘tails’  isn’t known. But in yeast, elevated levels are correlated with proteotoxic stress, a condition that in humans may be involved in disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease.”

Previously: Key to naked mole rat longevity may be related to their body’s ability to make proteins accurately and Night of the living dead gene: Pseudogene wakes up, puts chill on inflammation
Photo by Iain Farrell

Big data, Cancer, Cardiovascular Medicine, Fertility, Men's Health, Research, Stanford News

Male infertility can be warning of hypertension, Stanford study finds

Male infertility can be warning of hypertension, Stanford study finds

sperm graffitiA study of more than 9,000 men with fertility problems links poor semen quality to a higher chance of having hypertension and other health conditions. The findings suggest that more-comprehensive examinations of men undergoing treatment for infertility would be a smart idea.

About a quarter of the adults in the United States (and in the entire world) have hypertension, or high blood pressure. Although it’s the most important preventable risk factor for premature death worldwide, hypertension often goes undiagnosed.

In a study published today in Fertility and Sterility, Stanford urologist Mike Eisenberg, MD, PhD, and his colleagues analyzed the medical records of 9,387 men, mostly between 30 and 50 years old, who had provided semen samples in the course of being evaluated at Stanford to determine the cause of their infertility. The researchers found a substantial link between poor semen quality and specific diseases of the circulatory system, notably hypertension, vascular disease and heart disease.

“To the best of my knowledge, there’s never been a study showing this association before,” Eisenberg told me when I interviewed him for a press release about the findings. “There are a lot of men who have hypertension, so understanding that correlation is of huge interest to us.”

In the past few years, Eisenberg has used similar big data techniques to discover links between male infertility and cancer and heightened overall mortality, as well as between childlessness and death rates in married heterosexual men.

Eisenberg sums it all up and proposes a way forward in the release:

Infertility is a warning: Problems with reproduction may mean problems with overall health … That visit to a fertility clinic represents a big opportunity to improve their treatment for other conditions, which we now suspect could actually help resolve the infertility they came in for in the first place.

Previously: Poor semen quality linked to heightened mortality rate in men, Men with kids are at lower risk of dying from cardiovascular disease than their childless counterparts and Low sperm count can mean increased cancer risk
Photo by Grace Hebert

Immunology, Neuroscience, Research, Stanford News

Blocking a receptor on brain’s immune cells counters Alzheimer’s in mice

Blocking a receptor on brain’s immune cells counters Alzheimer’s in mice

brain in motionAttention, nerve cells: It’s not all about you.

As a new study in the Journal of Clinical Investigation led by Stanford neuroscientist Kati Andreasson, MD, shows, blocking the action of a single molecule situated on the surfaces of entirely different brain cells reversed memory loss and a bunch of other Alzheimer’s-like features in experimental mice.

The very term “neuroscience” strongly suggests that nerve cells, a.k.a. neurons, are the Big Enchilada in brain research – and, let’s face it, you wouldn’t want to leave home without them. But they’re far from the entire picture. In fact, neurons account for a mere 10 percent of all the cells in the brain. It may be that the mass die-off of nerve cells in the brains of people with Alzheimer’s disease may largely occur because, during the course of aging, another set of key players ensconced in that mysterious organ inside our skull and  known collectively as microglia begin to fall down on the job.

In  a release I wrote to explain the study’s findings in lay terms, I described microglia as the brain’s very own, dedicated immune cells:

A microglial cell serves as a front-line sentry, monitoring its surroundings for suspicious activities and materials by probing its local environment. If it spots trouble, it releases substances that recruit other microglia to the scene … Microglia are tough cops, protecting the brain against invading bacteria and viruses by gobbling them up. They are adept at calming things down, too, clamping down on inflammation if it gets out of hand. They also work as garbage collectors, chewing up dead cells and molecular debris strewn among living cells – including clusters of a protein called A-beta, notorious for aggregating into gummy deposits called Alzheimer’s plaques, the disease’s hallmark anatomical feature. … A-beta, produced throughout the body, is as natural as it is ubiquitous. But when it clumps into soluble clusters consisting of a few molecules, it’s highly toxic to nerve cells. These clusters are believed to play a substantial role in causing Alzheimer’s.

“The microglia are supposed to be, from the get-go, constantly clearing A-beta, as well as keeping a lid on inflammation,” Andreasson told me. If their job performance heads downhill – as seems to occur during the aging process – things get out of control. A-beta builds up in the brain, inducing toxic inflammation.

But by blocking the activity of a single molecule – a receptor protein on microglial cells’ surfaces  – Andreasson’s team got those microglia back on the job. They resumed chewing up A-beta, quashing runaway neuro-inflammation, squirting out neuron-nurturing chemicals. Bottom line: the Alzheimer’s-prone experimental animals’ IQs (as measured by mousey memory tests) rose dramatically.

Aspirin and similar drugs also tend to shut down the activity of this microglial receptor, which may or may not explain why their use seems to stave off the onset of Alzheimer’s in people who start using them regularly (typically for unrelated reasons) before this memory-stealing syndrome’s symptoms show up. But aspirin et al. do lots of other things, too – some good, some bad. The new findings suggest a compound carefully tailored to block this receptor and do nothing else might be a weapon in the anti-Alzheimer’s arsenal.

Previously: Another big step toward building a better aspirin tablet, Untangling the inflammation/Alzheimer’s connection and Study could lead to new class of stroke drugs
Photo by Henry Markham

Stanford Medicine Resources: