Posts Tagged ‘neurodegeneration’

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Senescent cells (represented here in green) no longer function but can broadcast inflammatory signals to the cells around them. These cells are implicated in a number of age-related diseases. Credit: The Mayo Clinic

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Darren Baker, Ph.D., a Mayo Clinic molecular biologist and senior author of the paper, and first author Tyler Bussian, a Mayo Clinic Graduate School of Biomedical Sciences student.

Zombie cells are the ones that can’t die but are equally unable to perform the functions of a normal cell. These zombie, or senescent, cells are implicated in a number of age-related diseases. And with a new letter in Nature, Mayo Clinic researchers have expanded that list.

In a mouse model of brain disease, scientists report that senescent cells accumulate in certain brain cells prior to cognitive loss. By preventing the accumulation of these cells, they were able to diminish tau protein aggregation, neuronal death and memory loss.

“Senescent cells are known to accumulate with advancing natural age and at sites related to diseases of aging, including osteoarthritis; atherosclerosis; and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s,” says Darren Baker, Ph.D., a Mayo Clinic molecular biologist and senior author of the paper. “In prior studies, we have found that elimination of senescent cells from naturally aged mice extends their healthy life span.”

In the current study, the team used a model that imitates aspects of Alzheimer’s disease.

“We used a mouse model that produces sticky, cobweb like tangles of tau protein in neurons and has genetic modifications to allow for senescent cell elimination,” explains first author Tyler Bussian, a Mayo Clinic Graduate School of Biomedical Sciences student who is part of Dr. Baker’s lab. “When senescent cells were removed, we found that the diseased animals retained the ability to form memories, eliminated signs of inflammation, did not develop neurofibrillary tangles, and had maintained normal brain mass.” They also report that pharmacological intervention to remove senescent cells modulated the clumping of tau proteins.

Also, the team was able to identify the specific type of cell that became senescent, says Dr. Baker.

“Two different brain cell types called ‘microglia’ and ‘astrocytes’ were found to be senescent when we looked at brain tissue under the microscope,” says Bussian. “These cells are important supporters of neuronal health and signaling, so it makes sense that senescence in either would negatively impact neuron health.”

The finding was somewhat surprising, explains Dr. Baker, because at the time their research started, a causal link between senescent cells and neurodegenerative disease had not been established.

“We had no idea whether senescent cells actively contributed to disease pathology in the brain, and to find that it’s the astrocytes and microglia that are prone to senescence is somewhat of a surprise, as well,” says Dr. Baker.

In terms of future work, Dr. Baker explains that this research lays out the best-case scenario, where prevention of damage to the brain avoided the disease state. “Clearly, this same approach cannot be applied clinically, so we are starting to treat animals after disease establishment and working on new models to examine the specific molecular alterations that occur in the affected cells,” says Dr. Baker.

In addition to Dr. Baker and Bussian, the other authors are Asef Aziz, a medical student formerly at Mayo Clinic; Charlton Meyer, Mayo Clinic; Barbara Swenson, Ph.D., Mayo Clinic; and Jan van Deursen, Ph.D., Mayo Clinic. Dr. van Deursen is the Vita Valley Professor of Cellular Senescence. Drs. Baker and van Deursen are inventors on patents licensed to Unity Biotechnology by Mayo Clinic, and Dr. van Deursen is a co-founder of Unity Biotechnology.

Funding for this research was provided by the Ellison Medical Foundation, the Glenn Foundation for Medical Research, the National Institutes of Health, the Mayo Clinic Children’s Research Center, and the Alzheimer’s Disease Research Center of Mayo Clinic.

https://newsnetwork.mayoclinic.org/discussion/senescent-cells-found-in-brains-of-mice-prior-to-cognitive-loss/

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by BRET STETKA

Dr. Leslie Norins is willing to hand over $1 million of his own money to anyone who can clarify something: Is Alzheimer’s disease, the most common form of dementia worldwide, caused by a germ?

By “germ” he means microbes like bacteria, viruses, fungi and parasites. In other words, Norins, a physician turned publisher, wants to know if Alzheimer’s is infectious.

It’s an idea that just a few years ago would’ve seemed to many an easy way to drain your research budget on bunk science. Money has poured into Alzheimer’s research for years, but until very recently not much of it went toward investigating infection in causing dementia.

But this “germ theory” of Alzheimer’s, as Norins calls it, has been fermenting in the literature for decades. Even early 20th century Czech physician Oskar Fischer — who, along with his German contemporary Dr. Alois Alzheimer, was integral in first describing the condition — noted a possible connection between the newly identified dementia and tuberculosis.

If the germ theory gets traction, even in some Alzheimer’s patients, it could trigger a seismic shift in how doctors understand and treat the disease.

For instance, would we see a day when dementia is prevented with a vaccine, or treated with antibiotics and antiviral medications? Norins thinks it’s worth looking into.

Norins received his medical degree from Duke in the early 1960s, and after a stint at the Centers for Disease Control and Prevention he fell into a lucrative career in medical publishing. He eventually settled in an admittedly aged community in Naples, Fla., where he took an interest in dementia and began reading up on the condition.

After scouring the medical literature he noticed a pattern.

“It appeared that many of the reported characteristics of Alzheimer’s disease were compatible with an infectious process,” Norins tells NPR. “I thought for sure this must have already been investigated, because millions and millions of dollars have been spent on Alzheimer’s research.”

But aside from scattered interest through the decades, this wasn’t the case.

In 2017, Norins launched Alzheimer’s Germ Quest Inc., a public benefit corporation he hopes will drive interest into the germ theory of Alzheimer’s, and through which his prize will be distributed. A white paper he penned for the site reads: “From a two-year review of the scientific literature, I believe it’s now clear that just one germ — identity not yet specified, and possibly not yet discovered — causes most AD. I’m calling it the ‘Alzheimer’s Germ.’ ”

Norins is quick to cite sources and studies supporting his claim, among them a 2010 study published in the Journal of Neurosurgery showing that neurosurgeons die from Alzheimer’s at a nearly 2 1/2 times higher rate than they do from other disorders.

Another study from that same year, published in The Journal of the American Geriatric Society, found that people whose spouses have dementia are at a 1.6 times greater risk for the condition themselves.

Contagion does come to mind. And Norins isn’t alone in his thinking.

In 2016, 32 researchers from universities around the world signed an editorial in the Journal of Alzheimer’s Disease calling for “further research on the role of infectious agents in [Alzheimer’s] causation.” Based on much of the same evidence Norins encountered, the authors concluded that clinical trials with antimicrobial drugs in Alzheimer’s are now justified.

NPR reported on an intriguing study published in Neuron in June that suggested that viral infection can influence the progression of Alzheimer’s. Led by Mount Sinai genetics professor Joel Dudley, the work was intended to compare the genomes of healthy brain tissue with that affected by dementia.

But something kept getting in the way: herpes.

Dudley’s team noticed an unexpectedly high level of viral DNA from two human herpes viruses, HHV-6 and HHV-7. The viruses are common and cause a rash called roseola in young children (not the sexually transmitted disease caused by other strains).

Some viruses have the ability to lie dormant in our neurons for decades by incorporating their genomes into our own. The classic example is chickenpox: A childhood viral infection resolves and lurks silently, returning years later as shingles, an excruciating rash. Like it or not, nearly all of us are chimeras with viral DNA speckling our genomes.

But having the herpes viruses alone doesn’t mean inevitable brain decline. After all, up to 75 percent of us may harbor HHV-6 .

But Dudley also noticed that herpes appeared to interact with human genes known to increase Alzheimer’s risk. Perhaps, he says, there is some toxic combination of genetic and infectious influence that results in the disease; a combination that sparks what some feel is the main contributor to the disease, an overactive immune system.

The hallmark pathology of Alzheimer’s is accumulation of a protein called amyloid in the brain. Many researchers have assumed these aggregates, or plaques, are simply a byproduct of some other process at the core of the disease. Other scientists posit that the protein itself contributes to the condition in some way.

The theory that amyloid is the root cause of Alzheimer’s is losing steam. But the protein may still contribute to the disease, even if it winds up being deemed infectious.

Work by Harvard neuroscientist Rudolph Tanzi suggests it might be a bit of both. Along with colleague Robert Moir, Tanzi has shown that amyloid is lethal to viruses and bacteria in the test tube, and also in mice. He now believes the protein is part of our ancient immune system that like antibodies, ramps up its activity to help fend off unwanted bugs.

So does that mean that the microbe is the cause of Alzheimer’s, and amyloid a harmless reaction to it? According to Tanzi it’s not that simple.

Tanzi believes that in many cases of Alzheimer’s, microbes are probably the initial seed that sets off a toxic tumble of molecular dominoes. Early in the disease amyloid protein builds up to fight infection, yet too much of the protein begins to impair function of neurons in the brain. The excess amyloid then causes another protein, called tau, to form tangles, which further harm brain cells.

But as Tanzi explains, the ultimate neurological insult in Alzheimer’s is the body’s reaction to this neurotoxic mess. All the excess protein revs up the immune system, causing inflammation — and it’s this inflammation that does the most damage to the Alzheimer’s-afflicted brain.

So what does this say about the future of treatment? Possibly a lot. Tanzi envisions a day when people are screened at, say, 50 years old. “If their brains are riddled with too much amyloid,” he says, “we knock it down a bit with antiviral medications. It’s just like how you are prescribed preventative drugs if your cholesterol is too high.”

Tanzi feels that microbes are just one possible seed for the complex pathology behind Alzheimer’s. Genetics may also play a role, as certain genes produce a type of amyloid more prone to clumping up. He also feels environmental factors like pollution might contribute.

Dr. James Burke, professor of medicine and psychiatry at Duke University’s Alzheimer’s Disease Research Center, isn’t willing to abandon the amyloid theory altogether, but agrees it’s time for the field to move on. “There may be many roads to developing Alzheimer’s disease and it would be shortsighted to focus just on amyloid and tau,” he says. “A million-dollar prize is attention- getting, but the reward for identifying a treatable target to delay or prevent Alzheimer’s disease is invaluable.”

Any treatment that disrupts the cascade leading to amyloid, tau and inflammation could theoretically benefit an at-risk brain. The vast majority of Alzheimer’s treatment trials have failed, including many targeting amyloid. But it could be that the patients included were too far along in their disease to reap any therapeutic benefit.

If a microbe is responsible for all or some cases of Alzheimer’s, perhaps future treatments or preventive approaches will prevent toxin protein buildup in the first place. Both Tanzi and Norins believe Alzheimer’s vaccines against viruses like herpes might one day become common practice.

In July of this year, in collaboration with Norins, the Infectious Diseases Society of America announced that they plan to offer two $50,000 grants supporting research into a microbial association with Alzheimer’s. According to Norins, this is the first acknowledgement by a leading infectious disease group that Alzheimer’s may be microbial in nature – or at least that it’s worth exploring.

“The important thing is not the amount of the money, which is a pittance compared with the $2 billion NIH spends on amyloid and tau research,” says Norins, “but rather the respectability and more mainstream status the grants confer on investigating of the infectious possibility. Remember when we thought ulcers were caused by stress?”

Ulcers, we now know, are caused by a germ.

https://www.npr.org/sections/health-shots/2018/09/09/645629133/infectious-theory-of-alzheimers-disease-draws-fresh-interest?ft=nprml&f=1001

By Jim Dryden

It may be possible in the future to screen patients for Alzheimer’s disease using an eye exam.

Using technology similar to what is found in many eye doctors’ offices, researchers at Washington University School of Medicine in St. Louis have detected evidence suggesting Alzheimer’s in older patients who had no symptoms of the disease.

Their study, involving 30 patients, is published Aug. 23 in the journal JAMA Ophthalmology.

“This technique has great potential to become a screening tool that helps decide who should undergo more expensive and invasive testing for Alzheimer’s disease prior to the appearance of clinical symptoms,” said the study’s first author, Bliss E. O’Bryhim, MD, PhD, a resident physician in the Department of Ophthalmology & Visual Sciences. “Our hope is to use this technique to understand who is accumulating abnormal proteins in the brain that may lead them to develop Alzheimer’s.”

Significant brain damage from Alzheimer’s disease can occur years before any symptoms such as memory loss and cognitive decline appear. Scientists estimate that Alzheimer’s-related plaques can build up in the brain two decades before the onset of symptoms, so researchers have been looking for ways to detect the disease sooner.

Physicians now use PET scans and lumbar punctures to help diagnose Alzheimer’s, but they are expensive and invasive.

In previous studies, researchers examining the eyes of people who had died from Alzheimer’s have reported that the eyes of such patients showed signs of thinning in the center of the retina and degradation of the optic nerve.

In the new study, the researchers used a noninvasive technique — called optical coherence tomography angiography — to examine the retinas in eyes of 30 study participants with an average age in the mid 70s, none of whom exhibited clinical symptoms of Alzheimer’s.

Those participants were patients in The Memory and Aging Project at Washington University’s Knight Alzheimer’s Disease Research Center. About half of those in the study had elevated levels of the Alzheimer’s proteins amyloid or tau as revealed by PET scans or cerebrospinal fluid, suggesting that although they didn’t have symptoms, they likely would develop Alzheimer’s. In the other subjects, PET scans and cerebrospinal fluid analyses were normal.

“In the patients with elevated levels of amyloid or tau, we detected significant thinning in the center of the retina,” said co-principal investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences. “All of us have a small area devoid of blood vessels in the center of our retinas that is responsible for our most precise vision. We found that this zone lacking blood vessels was significantly enlarged in people with preclinical Alzheimer’s disease.”

The eye test used in the study shines light into the eye, allowing a doctor to measure retinal thickness, as well as the thickness of fibers in the optic nerve. A form of that test often is available in ophthalmologist’s offices.

For this study, however, the researchers added a new component to the more common test: angiography, which allows doctors to distinguish red blood cells from other tissue in the retina.

“The angiography component allows us to look at blood-flow patterns,” said the other co-principal investigator, Gregory P. Van Stavern, MD, a professor of ophthalmology and visual sciences. “In the patients whose PET scans and cerebrospinal fluid showed preclinical Alzheimer’s, the area at the center of the retina without blood vessels was significantly larger, suggesting less blood flow.”

Added Apte: “The retina and central nervous system are so interconnected that changes in the brain could be reflected in cells in the retina.”

Of the patients studied, 17 had abnormal PET scans and/or lumbar punctures, and all of them also had retinal thinning and significant areas without blood vessels in the centers of their retinas. The retinas appeared normal in the patients whose PET scans and lumbar punctures were within the typical range.

More studies in patients are needed to replicate the findings, Van Stavern said, but he noted that if changes detected with this eye test can be used as markers for Alzheimer’s risk, it may be possible one day to screen people as young as their 40s or 50s to see whether they are at risk for the disease.

“We know the pathology of Alzheimer’s disease starts to develop years before symptoms appear, but if we could use this eye test to notice when the pathology is beginning, it may be possible one day to start treatments sooner to delay further damage,” he said.

O’Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP. Optical coherence tomography angiography findings in pre-clinical Alzheimer’s disease. JAMA Ophthalmology, Aug. 23, 2018.

https://source.wustl.edu/2018/08/alzheimers-one-day-may-be-predicted-during-eye-exam/


Reprinted from The Lancet Neurology, http://dx.doi.org/10.1016/S1474-4422(18)30245-X, Trapp et al, Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study, Copyright (2018), with permission from Elsevier


Bruce Trapp, Ph.D., chair of Cleveland Clinic’s Lerner Research Institute Department of Neurosciences

Cleveland Clinic researchers have discovered a new subtype of multiple sclerosis (MS), providing a better understanding of the individualized nature of the disease.

MS has long been characterized as a disease of the brain’s white matter, where immune cells destroy myelin – the fatty protective covering on nerve cells. The destruction of myelin (called demyelination) was believed to be responsible for nerve cell (neuron) death that leads to irreversible disability in patients with MS.

However, in the new findings, a research team led by Bruce Trapp, Ph.D., identified for the first time a subtype of the disease that features neuronal loss but no demyelination of the brain’s white matter. The findings, published in Lancet Neurology, could potentially lead to more personalized diagnosis and treatments.

The team’s findings support the concept that neurodegeneration and demyelination can occur independently in MS and underscore the need for more sensitive MRI imaging techniques for evaluating brain pathology in real time and monitoring treatment response in patients with the disease. This new subtype of MS, called myelocortical MS (MCMS), was indistinguishable from traditional MS on MRI. The researchers observed that in MCMS, part of the neurons become swollen and look like typical MS lesions indicative of white matter myelin loss on MRI. The disease was only diagnosed in post-mortem tissues.

“This study opens up a new arena in MS research. It is the first to provide pathological evidence that neuronal degeneration can occur without white matter myelin loss in the brains of patients with the disease,” said Trapp, chair of Cleveland Clinic’s Lerner Research Institute Department of Neurosciences. “This information highlights the need for combination therapies to stop disability progression in MS.”

In the study of brain tissue from 100 MS patients who donated their brains after death, the researchers observed that 12 brains did not have white matter demyelination. They compared microscopic tissue characteristics from the brains and spinal cords of 12 MCMS patients, 12 traditional MS patients and also individuals without neurological disease. Although both MCMS and traditional MS patients had typical MS lesions in the spinal cord and cerebral cortex, only the latter group had MS lesions in the brain white matter.

Despite having no typical MS lesions in the white matter, MCMS brains did have reduced neuronal density and cortical thickness, which are hallmarks of brain degeneration also observed in traditional MS. Contrary to previous belief, these observations show that neuronal loss can occur independently of white matter demyelination.

“The importance of this research is two-fold. The identification of this new MS subtype highlights the need to develop more sensitive strategies for properly diagnosing and understanding the pathology of MCMS,” said Daniel Ontaneda, M.D., clinical director of the brain donation program at Cleveland Clinic’s Mellen Center for Treatment and Research in MS. “We are hopeful these findings will lead to new tailored treatment strategies for patients living with different forms of MS.”

Dr. Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in MS and has published more than 240 peer-reviewed articles and 40 book chapters. He also holds the Morris R. and Ruth V. Graham Endowed Chair in Biomedical Research. In 2017 he received the prestigious Outstanding Investigator award by the National Institute of Neurological Disorders and Stroke to examine the biology of MS and to seek treatments that could slow or reverse the disease.

https://newsroom.clevelandclinic.org/2018/08/21/cleveland-clinic-researchers-discover-novel-subtype-of-multiple-sclerosis/

by Judy George

Retinal thinning was linked to dopaminergic neuronal atrophy in a cross-sectional analysis, raising the possibility that it could be a way to detect pathologic changes in early Parkinson’s disease (PD) patients, researchers said.

Drug-naïve patients with early Parkinson’s showed retinal thinning as measured by optical coherence tomography (OCT) that correlated with both disease severity and nigral dopaminergic degeneration, reported Jee-Young Lee, MD, PhD, of the Seoul National University Boramae Medical Center, and colleagues in Neurology.

“Our study is the first to show a link between the thinning of the retina and a known sign of the progression of the disease — the loss of brain cells that produce dopamine,” Lee said in a statement.

“We also found the thinner the retina, the greater the severity of disease. These discoveries may mean that neurologists may eventually be able to use a simple eye scan to detect Parkinson’s disease in its earliest stages, before problems with movement begin.”

Retinal pathology has been tied to other neurodegenerative disorders including dementia. In previous studies, retinal nerve fiber layer thickness has been linked to Parkinson’s disease, and OCT is a potential PD biomarker.

The search for a definitive Parkinson’s biomarker has been extensive and includes clinical (anosmia; REM behavior disorder), genetic (GBA mutation; LRRK2 mutation), and biochemical (blood and cerebrospinal fluid) techniques, along with positron emission tomography (PET), magnetic resonance imaging (MRI), and single photon emission computed tomography (SPECT) imaging.

No biomarker has been validated for clinical practice, noted Jamie Adams, MD, of the University of Rochester Medical Center in New York, and Chiara La Morgia, MD, PhD, of the University of Bologna in Italy, in an accompanying editorial: “Because of the complexity of the disease, combining biomarkers from different categories is likely the best strategy to accurately predict PD status and progression.”

In this analysis, Lee and colleagues studied 49 Parkinson’s patients with an average age of 69, along with 54 age-matched controls, including only early-stage, drug-naïve PD patients without ophthalmologic disease.

The researchers used high-resolution OCT to measure retinal nerve fiber layer thickness, microperimetry to measure retinal function, and dopamine transporter analysis to measure N(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane uptake in the basal ganglia. Retinal layer thickness and volume were measured and compared in PD patients and controls.

Retinal thinning was found in the inferior and temporal perifoveal sectors of the PD patients, particularly the inner plexiform and ganglion cell layers, along with an association between retinal thinning and dopaminergic loss in the left substantia nigra. The team also reported an inverse association between inner retinal thickness in the inferior perifoveal sector and disease severity (Hoehn and Yahr stage), and a positive correlation between macular sensitivity and retinal layer thickness.

“Overall, these data support the presence of an association between retinal thinning and dopaminergic loss in PD,” said Adams and La Morgia. “Inner retinal thinning in individuals with PD has been reported in previous studies, but this is the first study that demonstrates a correlation between inner retinal thinning and nigral dopaminergic loss.”

“These findings may point to a pathologic connection between the retina and basal ganglia in PD and are in line with previous studies reporting asymmetric retinal nerve fiber layer loss, more evident in the eye contralateral to the most affected body side.”

The results need to be interpreted with caution, Lee and co-authors noted. Retina analysis was limited to the macular area in this research. Studies with larger numbers of Parkinson’s patients are needed to confirm the findings. And this study was a cross-sectional analysis, so correlations between retinal changes and PD severity need to be established over time.

But if the findings are confirmed, “retina scans may not only allow earlier treatment of Parkinson’s disease, but more precise monitoring of treatments that could slow progression of the disease as well,” Lee said.

https://www.medpagetoday.com/neurology/parkinsonsdisease/74575


Age-related macular degeneration, diabetic retinopathy and glaucoma were all associated with a higher risk of developing Alzheimer’s disease in a new study.

by Rich Haridy

A new study has found an interesting correlation between several degenerative eye diseases and the onset of Alzheimer’s disease. No mechanism explaining the connection has been proposed at this stage but it is thought these eye conditions may help physicians identify patients at risk of developing Alzheimer’s at a stage before major symptoms appear.

The five-year study followed almost 4,000 patients over the age of 65, all without clinically diagnosed Alzheimer’s disease at the time of enrolment. After five years, 792 subjects were officially diagnosed with Alzheimer’s. The study found that those subjects with age-related macular degeneration, diabetic retinopathy or glaucoma, were 40 to 50 percent more likely to develop Alzheimer’s compared to patients without those specific conditions. No correlation between cataracts and an increased risk of Alzheimer’s were found.

“We don’t mean people with these eye conditions will get Alzheimer’s disease,” cautions Cecilia Lee, lead researcher on the study. “The main message from this study is that ophthalmologists should be more aware of the risks of developing dementia for people with these eye conditions and primary care doctors seeing patients with these eye conditions might be more careful on checking on possible dementia or memory loss.”

The researchers are clear that there are no definable causal connections between these eye conditions and Alzheimer’s at this stage, but the study does highlight the potential of using the eye as a way to better understand what is going on in the brain. Intriguingly, this isn’t the first bit of research that has found correlations between signs detected in the eye and the onset of Alzheimer’s disease.

Last year, a team from Cedars-Sinai Medical Center revealed that the same type of amyloid protein deposits found in the brain, and hypothesized as a major pathogenic cause of Alzheimer’s, can also be detected on the retina. That research suggested a possible investigational eye scan could become an effective early screening device for the disease.

While this new study does not at all cross over with last year’s research, and there is no implication that amyloid proteins play a part in these degenerative eye diseases, it does add to a fascinating growing body of work that highlights the eye’s role in helping offer a deeper insight into the cognitive health of our brain.

The research was published in the journal Alzheimer’s & Dementia.

https://newatlas.com/eye-disease-alzheimers-connection/55823/


Illustration of how pH imbalance inside endosomes may contribute to Alzheimer’s disease

Johns Hopkins Medicine scientists say they have found new evidence in lab-grown mouse brain cells, called astrocytes, that one root of Alzheimer’s disease may be a simple imbalance in acid-alkaline—or pH—chemistry inside endosomes, the nutrient and chemical cargo shuttles in cells.

Astrocytes work to clear so-called amyloid beta proteins from the spaces between neurons, but decades of evidence has shown that if the clearing process goes awry, amyloid proteins pile up around neurons, leading to the characteristic amyloid plaques and nerve cell degeneration that are the hallmarks of memory-destroying Alzheimer’s disease.

The new study, described online June 26 in Proceedings of the National Academy of Sciences, also reports that the scientists gave drugs called histone deacetylase (HDAC) inhibitors to pH-imbalanced mice cells engineered with a common Alzheimer’s gene variant. The experiment successfully reversed the pH problem and improved the capacity for amyloid beta clearance.

HDAC inhibitors are approved by the U.S. Food and Drug Administration for use in people with certain types of blood cancers, but not in people with Alzheimer’s. They cautioned that most HDAC inhibitors cannot cross the blood-brain barrier, a significant challenge to the direct use of the drugs for brain disorders. The scientists say they are planning additional experiments to see if HDAC inhibitors have a similar effect in lab-grown astrocytes from Alzheimer’s patients, and that there is the potential to design HDAC inhibitors that can cross the barrier.

However, the scientists caution that even before those experiments can happen, far more research is needed to verify and explain the precise relationship between amyloid proteins and Alzheimer’s disease, which affects an estimated 50 million people worldwide. To date, there is no cure and no drugs that can predictably or demonstrably prevent or reverse Alzheimer’s disease symptoms.

“By the time Alzheimer’s disease is diagnosed, most of the neurological damage is done, and it’s likely too late to reverse the disease’s progression,” says Rajini Rao, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine. “That’s why we need to focus on the earliest pathological symptoms or markers of Alzheimer’s disease, and we know that the biology and chemistry of endosomes is an important factor long before cognitive decline sets in.”

Nearly 20 years ago, scientists at Johns Hopkins and New York University discovered that endosomes, circular compartments that ferry cargo within cells, are larger and far more abundant in brain cells of people destined to develop Alzheimer’s disease. This hinted at an underlying problem with endosomes that could lead to an accumulation of amyloid protein in spaces around neurons, says Rao.

To shuttle their cargo from place to place, endosomes use chaperones—proteins that bind to specific cargo and bring them back and forth from the cell’s surface. Whether and how well this binding occurs depends on the proper pH level inside the endosome, a delicate balance of acidity and alkalinity, or acid and base, that makes endosomes float to the surface and slip back down into the cell.

Embedded in the endosome membrane are proteins that shuttle charged hydrogen atoms, known as protons, in and out of endosomes. The amount of protons inside the endosome determines its pH.

When fluids in the endosome become too acidic, the cargo is trapped within the endosome deep inside the cell. When the endosome contents are more alkaline, the cargo lingers at the cell’s surface for too long.

To help determine whether such pH imbalances occur in Alzheimer’s disease, Johns Hopkins graduate student Hari Prasad scoured scientific studies of Alzheimer’s disease looking for genes that were dialed down in diseased brains compared with normal ones. Comparing a dataset of 15 brains of Alzheimer’s disease patients with 12 normal ones, he found that 10 of the 100 most frequently down-regulated genes were related to the proton flow in the cell.

In another set of brain tissue samples from 96 people with Alzheimer’s disease and 82 without it, gene expression of the proton shuttle in endosomes, known as NHE6, was approximately 50 percent lower in people with Alzheimer’s disease compared with those with normal brains. In cells grown from people with Alzheimer’s disease and in mouse astrocytes engineered to carry a human Alzheimer’s disease gene variant, the amount of NHE6 was about half the amount found in normal cells.

To measure the pH balance within endosomes without breaking open the astrocyte, Prasad and Rao used pH sensitive probes that are absorbed by endosomes and emit light based on pH levels. They found that mouse cell lines containing the Alzheimer’s disease gene variant had more acidic endosomes (average of 5.37 pH) than cell lines without the gene variant (average of 6.21 pH).

“Without properly functioning NHE6, endosomes become too acidic and linger inside astrocytes, avoiding their duties to clear amyloid beta proteins,” says Rao.

While it’s likely that changes in NHE6 happen over time in people who develop sporadic Alzheimer’s disease, people who have inherited mutations in NHE6 develop what’s known as Christianson syndrome in infancy and have rapid brain degeneration.

Prasad and Rao also found that a protein called LRP1, which picks up amyloid beta proteins outside the astrocyte and delivers them to endosomes, was half as abundant on the surface of lab grown mouse astrocytes engineered with a human gene variant called APOE4, commonly linked to Alzheimer’s disease.

Looking for ways to restore the function of NHE6, Prasad searched databases of yeast studies to find that HDAC inhibitors tend to increase expression of the NHE6 gene in yeast. This gene is very similar across species, including flies, mice and humans.

Prasad and Rao tested nine types of HDAC inhibitors on cell cultures of mouse astrocytes engineered with the APOE4 gene variant. Broad-spectrum HDAC inhibitors increased NHE6 expression to levels associated with mouse astrocytes that did not have the Alzheimer’s gene variant. They also found that HDAC inhibitors corrected the pH imbalance inside endosomes and restored LRP1 to the astrocyte surface, resulting in efficient clearance of amyloid beta protein.

More information: Hari Prasad et al. Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1801612115

https://medicalxpress.com/news/2018-08-ph-imbalance-brain-cells-contribute.html