Tag: acid

pH imbalance in brain cells may contribute to Alzheimer’s disease

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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

How LSD Makes Your Brain One With The Universe

On By A.P.In brain, Drugs, hallucination, hallucinations, LSD, lysergic acid diethylamaide, Psilocybin2 Comments

lsd

by Angus Chen

Some users of LSD say one of the most profound parts of the experience is a deep oneness with the universe. The hallucinogenic drug might be causing this by blurring boundaries in the brain, too.

The sensation that the boundaries between yourself and the world around you are erasing correlates to changes in brain connectivity while on LSD, according to a study published Wednesday in Current Biology. Scientists gave 15 volunteers either a drop of acid or a placebo and slid them into an MRI scanner to monitor brain activity.

After about an hour, when the high begins peaking, the brains of people on acid looked markedly different than those on the placebo. For those on LSD, activity in certain areas of their brain, particularly areas rich in neurons associated with serotonin, ramped up.

Their sensory cortices, which process sensations like sight and touch, became far more connected than usual to the frontal parietal network, which is involved with our sense of self. “The stronger that communication, the stronger the experience of the dissolution [of self],” says Enzo Tagliazucchi, the lead author and a researcher at the Netherlands Institute for Neuroscience.

Tagliazucchi speculates that what’s happening is a confusion of information. Your brain on acid, flooded with signals crisscrossing between these regions, begins muddling the things you see, feel, taste or hear around you with you. This can create the perception that you and, say, the pizza you’re eating are no longer separate entities. You are the pizza and the world beyond the windowsill. You are the church and the tree and the hill.

Albert Hofmann, the discoverer of LSD, described this in his book LSD: My Problem Child. “A portion of the self overflows into the outer world, into objects, which begin to live, to have another, a deeper meaning,” he wrote. He felt the world would be a better place if more people understood this. “What is needed today is a fundamental re-experience of the oneness of all living things.”

The sensation is neurologically similar to synesthesia, Tagliazucchi thinks. “In synesthesia, you mix up sensory modalities. You can feel the color of a sound or smell the sound. This happens in LSD, too,” Tagliazucchi says. “And ego dissolution is a form of synesthesia, but it’s a synesthesia of areas of brain with consciousness of self and the external environment. You lose track of which is which.”

Tagliazucchi and other researchers also measured the volunteers’ brain electrical activity with another device. Our brains normally generate a regular rhythm of electrical activity called the alpha rhythm, which links to our brain’s ability to suppress irrelevant activity. But in a different paper published on Monday in the Proceedings of the National Academy of Sciences, he and several co-authors show that LSD weakens the alpha rhythm. He thinks this weakening could make the hallucinations seem more real.

The idea is intriguing if still somewhat speculative, says Dr. Charles Grob, a psychiatrist at the Harbor-UCLA Medical Center who was not involved with the work. “They may genuinely be on to something. This should really further our understanding of the brain and consciousness.” And, he says, the work highlights hallucinogens’ powerful therapeutic potential.

The altered state of reality that comes with psychedelics might enhance psychotherapy, Grob thinks. “Hallucinogens are a catalyst,” he says. “In well-prepared subjects, you might elicit powerful, altered states of consciousness. [That] has been predicative of positive therapeutic outcomes.”

In recent years, psychedelics have been trickling their way back to psychiatric research. LSD was considered a good candidate for psychiatric treatment until 1966, when it was outlawed and became very difficult to obtain for study. Grob has done work testing the treatment potential of psilocybin, the active compound in hallucinogenic mushrooms.

He imagines a future where psychedelics are commonly used to treat a range of conditions. “[There could] be a peaceful room attractively fixed up with nice paintings, objects to look at, fresh flowers, a chair or recliner for the patient and two therapists in the room,” he muses. “A safe container for that individual as they explore deep inner space, inner terrain.”

Grob believes the right candidate would benefit greatly from LSD or other hallucinogen therapy, though he cautions that bad experiences can still happen for some on the drugs. Those who are at risk for schizophrenia may want to avoid psychedelics, Tagliazucchi says. “There has been evidence saying what could happen is LSD could trigger the disease and turn it into full-fledged schizophrenia,” he says. “There is a lot of debate around this. It’s an open topic.”

Tagliazucchi thinks that this particular ability of psychedelics to evoke a sense of dissolution of self and unity with the external environment has already helped some patients. “Psilocybin has been used to treat anxiety with terminal cancer patients,” he says. “One reason why they felt so good after treatment is the ego dissolution is they become part of something larger: the universe. This led them to a new perspective on their death.”

http://www.npr.org/sections/health-shots/2016/04/13/474071268/how-lsd-makes-your-brain-one-with-the-universe

How LSD works in the brain

On By A.P.In ayahuasca, DMT, Drugs, hallucinogen, ibogaine, LSD, lysergic acid diethylamaide, mescaline, Neuroscience, peyote, psilocin, Psilocybin, salvia divinorumLeave a comment

by Natalie Wolchover

The main theory of psychedelics, first fleshed out by a Swiss researcher named Franz Vollenweider, is that drugs like LSD and psilocybin, the active ingredient in “magic” mushrooms, tune down the thalamus’ activity. Essentially, the thalamus on a psychedelic drug lets unprocessed information through to consciousness, like a bad email spam filter. “Colors become brighter , people see things they never noticed before and make associations that they never made before,” Sewell said.

LSD, or acid, and its mind-bending effects have been made famous by pop culture hits like “Fear and Loathing in Las Vegas,” a film about the psychedelic escapades of writer Hunter S. Thompson. Oversaturated colors, swirling walls and intense emotions all supposedly come into play when you’re tripping. But how does acid make people trip?

Life’s Little Mysteries asked Andrew Sewell, a Yale psychiatrist and one of the few U.S.-based psychedelic drug researchers, to explain why LSD short for lysergic acid diethylamide does what it does to the brain.

His explanation begins with a brief rundown of how the brain processes information under normal circumstances. It all starts in the thalamus, a node perched on top of the brain stem, right smack dab in the middle of the brain. “Most sensory impressions are routed through the thalamus, which acts as a gatekeeper, determining what’s relevant and what isn’t and deciding where the signals should go,” Sewell said.

“Consequently, your perception of the world is governed by a combination of ‘bottom-up’ processing, starting … with incoming signals, combined with ‘top-down’ processing, in which selective filters are applied by your brain to cut down the overwhelming amount of information to a more manageable and relevant subset that you can then make decisions about.

“In other words, people tend to see what they’ve been trained to see, and hear what they’ve been trained to hear.”

The main theory of psychedelics, first fleshed out by a Swiss researcher named Franz Vollenweider, is that drugs like LSD and psilocybin, the active ingredient in “magic” mushrooms, tune down the thalamus’ activity. Essentially, the thalamus on a psychedelic drug lets unprocessed information through to consciousness, like a bad email spam filter. “Colors become brighter , people see things they never noticed before and make associations that they never made before,” Sewell said.

n a recent paper advocating the revival of psychedelic drug research, psychiatrist Ben Sessa of the University of Bristol in England explained the benefits that psychedelics lend to creativity. “A particular feature of the experience is … a general increase in complexity and openness, such that the usual ego-bound restraints that allow humans to accept given pre-conceived ideas about themselves and the world around them are necessarily challenged. Another important feature is the tendency for users to assign unique and novel meanings to their experience together with an appreciation that they are part of a bigger, universal cosmic oneness.”

But according to Sewell, these unique feelings and experiences come at a price: “disorganization, and an increased likelihood of being overwhelmed.” At least until the drugs wear off, and then you’re left just trying to make sense of it all.

http://www.livescience.com/33167-how-acid-lsd-make-people-trip.html?li_source=pm&li_medium=most-popular&li_campaign=related_test