Tag Archives: Alzheimer’s

How to Clear Brain Plaques with Light and Oxygen to Prevent Alzheimer’s

A small, light-activated molecule recently tested in mice represents a new approach to eliminating clumps of amyloid protein found in the brains of Alzheimer’s disease patients. If perfected in humans, the technique could be used as an alternative approach to immunotherapy and used to treat other diseases caused by similar amyloids. Researchers injected the molecule directly into the brains of live mice with Alzheimer’s disease and then used a specialized probe to shine light into their brains for 30 minutes each day for one week. Chemical analysis of the mouse brain tissue showed that the treatment significantly reduced amyloid protein. Results from additional experiments using human brain samples donated by Alzheimer’s disease patients supported the possibility of future use in humans.

The importance of our study is developing this technique to target the amyloid protein to enhance clearance of it by the immune system,” said Yukiko Hori, a lecturer at the University of Tokyo and co-first author of the research recently published in Brain. The small molecule that the research team developed is known as a photo-oxygenation catalyst. It appears to treat Alzheimer’s disease via a two-step process.

First, the catalyst destabilizes the amyloid plaques. Oxygenation, or adding oxygen atoms, can make a molecule unstable by changing the chemical bonds holding it together. Laundry detergents or other cleaners known as “oxygen bleach” use a similar chemical principle. The catalyst is designed to target the folded structure of amyloid and likely works by cross-linking specific portions called histidine residues. The catalyst is inert until it is activated with near-infrared light, so in the future, researchers imagine that the catalyst could be delivered throughout the body by injection into the bloodstream and targeted to specific areas using light.

Second, the destabilized amyloid is then removed by microglia, immune cells of the brain that clear away damaged cells and debris outside healthy cells. Using mouse cells growing in a dish, researchers observed microglia engulfing oxygenated amyloid and then breaking it down in acidic compartments inside the cells. “Our catalyst binds to the amyloid-specific structure, not to a unique genetic or amino acid sequence, so this same catalyst can be applied to other amyloid depositions,” said Professor Taisuke Tomita, who led the project at the University of Tokyo.

The American Society of Clinical Oncology estimates that each year in the U.S., 4,000 people are diagnosed with diseases caused by amyloid outside of the brain, collectively known as amyloidosis. The photo-oxygenation catalyst should be capable of removing amyloid protein, regardless of when or where it formed in the body. Although some existing Alzheimer’s disease treatments can slow the formation of new amyloid plaques, eliminating existing plaques is especially important in Alzheimer’s disease because amyloid begins aggregating years before symptoms appear.

Source: https://www.u-tokyo.ac.jp/

Neuralink Wants to Implant Human Brain Chips Within a Year

Tesla CEO Elon Musk released a video showing how his company Neuralink – a brain-computer-interface company – had advanced its technology to the point that the chip could allow a monkey to play video games with its mind.


Neuralink could transition from operating on monkeys to human trials within the year, if the startup meets a previous prediction from Musk. In February, he said the company planned to launch human trials by the end of the year after first mentioning his work with the monkey implants.

At the time, the CEO gave the timeline in response to another user’s request to join human trials for the product, which is designed to implant artificial intelligence into human brains as well as potentially cure neurological diseases like Alzheimer’s and Parkinson’s.

Musk has made similar statements in the past about his project, which was launched in 2016. He said in 2019 that it would be testing on humans by the end of 2020.

There has been a recent flurry of information on the project. Prior to the recent video release on Twitter, Musk had made an appearance on the social media site, Clubhouse, and provided some additional updates on Neuralink back in February.

During his Clubhouse visit, Musk detailed how the company had implanted the chip in the monkey’s brain and talked about how it could play video games using only its mind.

Source: https://www.sciencealert.com/

A Cannabis Molecule Reduces Plaque, Improves Cognition in Alzheimer’s

A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report. The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.

The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia (DCG) and the study’s corresponding author. There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia (MCG) investigators write in the Journal of Alzheimer’s Disease.

Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. “One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.

The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.

They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system, he says.

CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.

Source: https://jagwire.augusta.edu/

Base Editing Could Cure a Host of Genetic Diseases

Picture the familiar double helix of human DNA — a long, twisted ladder with 3 billion rungs on it, each made of a pair of genetic bases (A, T, C, and G). A mistake in just one base along that ladderan A where there should be a G — can be enough to cause a disease. In fact, researchers have linked over 31,000 different mistakes, known as “point mutations,” to human diseases. Now, an advanced form of gene therapy — called base editing — could make it possible to safely correct them.

Base editing is a type of gene editing technology, just like CRISPR. However, while CRISPR cuts through both strands of the DNA ladder to swap in different genes, a base editor makes precise changes to individual letters along the genome — a much less invasive kind of DNA surgery.

It’s like your spell-checker,” neuroscientist Jeffrey Holt said. “If you type the wrong letter, spell checker fixes it for you.” Base editing was first developed by Broad Institute researcher David Liu in 2016, and it’s not perfect — the best base editors still make off-target edits and aren’t 100%  efficient. However, the technique is more efficient than CRISPR and causes fewer errors, which has made it the focus of considerable research into correcting disease-causing point mutations.

Base editing is like your spell-checker. If you type the wrong letter, it fixes it for you,” explained Jeffrey Holt. Holt was part of a team that used base editing to partially restore the hearing of mice with a point mutation that causes deafness in people. Earlier in 2020, University of Illinois researchers used base editing to slow the progression of ALS in mice. More recently, Liu was part of a group that used base editing to correct the point mutation that causes progeria, a premature-aging syndrome, in mice. By changing a T to a C in a single gene, they were able to more than double the lifespan of mice with the disease.

There’s no guarantee that a therapy that works in mice will translate to humans (although gene editing is conceptually much simpler than drugs that rely on complex chemistry). To find out whether base editing can live up to its promise as a disease-curing technology, we need human studies — and now, one is just on the horizon.

On January 12, Massachusetts-based biotech company Verve Therapeutics announced the promising results of a study testing a base editing treatment for heterozygous familial hypercholesterolemia (HeFH), a genetic heart diseaseHeFH is fairly common, affecting about one in 500 people, and it causes consistently high levels of “badcholesterol (LDL-C) — that makes people with the disease susceptible to heart attacks or strokes at a relatively young age. In primates with HeFH, Verve used base editing to change an A to a G in a single gene. Within two weeks, the animals’ blood LDL-C levels had dropped by 59%. Six months later, they were still just as low.The treatment, dubbed “VERVE-101,” was well-tolerated, with no adverse effects reported.

When we started, we had no idea this would work,” Verve CEO Sekar Kathiresan said in a press release, adding, “It works, and we expect this to be durable for the lifetime of the animals.” Now, Verve wants to find out if VERVE-101 works in humans.

Source: https://www.freethink.com/

Immune System Killer Cells Controlled By Circadian Rhythms

An analysis of an exhaustive dataset on cells essential to the mammalian immune system shows that our ability to fight disease may rely more heavily on daily circadian cycles than previously assumed.

Malfunctions in , the process that keeps our bodies in tune with the day/night cycles, are increasingly associated with diabetes, cancer, Alzheimer’s, and many other diseases. An investigation published today in Genome Research shows that the activity of macrophagescells within us that seek and destroy intruders like bacteria—may time daily changes in their responses to pathogens and stress through the circadian control of metabolism. In this study, Jennifer Hurley, the Richard Baruch M.D. Career Development Assistant Professor of Biological Sciences at Rensselaer Polytechnic Institute and senior author on this study, and her team investigated how the levels of RNA and proteins in macrophages change over two days.

We have shown there is an incredible amount of circadian timing of macrophage behavior, but the clock is timing macrophages in unexpected ways” said Hurley.

The circadian system is comprised of a set of core clock proteins that anticipate the day/night cycle by causing daily oscillations in levels of enzymes and hormones, and ultimately affecting physiological parameters such as body temperature and the immune response. This molecular clock marks time through a self-regulating cycle of  production and decay. The “positive” element proteins of the clock trigger production of the “negative” element proteins, which in turn block production of positive element proteins until the negative element proteins decay, thus creating a negative feedback cycle that occurs once every 24 hours.

Positive element proteins also regulate fluctuations in a substantial number of gene products, known as messenger RNA or mRNA. Genetic instructions are transcribed from DNA to mRNA, which are then used as a recipe for assembling proteins, the functional building blocks of the cell. It has long been assumed that the levels of each subsequent step could be predicted from the previous. If that were the case, oscillating mRNA would correspond with oscillating levels of cellular proteins, and therefore, if one could track mRNA, they would know what proteins the circadian clock controlled in the cell.

However, this investigation showed that this paradigm may not always be true. The analysis of the macrophage dataset revealed that there was a substantial mismatch between the proteins and mRNAs that are controlled by the circadian clock. This data paralleled research published in Cell Systems in 2018 by the Hurley lab, showing that about 40% of oscillating proteins in the fungus and circadian model system, Neurospora crassa, had no corresponding oscillating mRNA.

But the scale of the difference in macrophages really surprised us,” Hurley said. “Eighty percent of the proteins that oscillate don’t have associated oscillating mRNA in macrophages. That means we were really missing how the clock was timing immunity.”

Source: https://medicalxpress.com/

Alzheimer’s Is Actually 3 Distinct Disease Subtypes

Alzheimer’s Disease (AD) is probably more diverse than our traditional models suggest. Postmortem, RNA sequencing has revealed three major molecular subtypes of the disease, each of which presents differently in the brain and which holds a unique genetic risk.  Such knowledge could help us predict who is most vulnerable to each subtype, how their disease might progress and what treatments might suit them best, potentially leading to better outcomes. It could also help explain why effective treatments for AD have proved so challenging to find thus far.

The mouse models we currently have for pharmaceutical research match a particular subset of AD,  but not all subtypes simultaneouslyThis may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalised human trials across all AD subtypes,”  say the authors. “Therefore,” the authors conclude, “subtyping patients with AD is a critical step toward precision medicine for this devastating disease.

Traditionally, AD is thought to be marked by clumps of amyloid-beta plaques (), as well as tangles of tau proteins (NFTs) found in postmortem biopsies of the brain. Both of these markers have become synonymous with the disease, but in recent years our leading hypotheses about what they actually do to our brains have come under question. Typically, accumulations of and NFT are thought to drive neuronal and synaptic loss, predominantly within the cerebral cortex and hippocampus. Further degeneration then follows, including inflammation and degeneration of nerve cells‘ protective coating, which causes signals in our brains to slow down.

Strangely enough, however, recent evidence has shown up to a third of patients with a confirmed, clinical diagnosis have no Aβ plaques in postmortem biopsies. What’s more, many of those found with plaques at death did not show cognitive impairment in life. Instead of being an early trigger of AD, setting off neurodegeneration and driving memory loss and confusion, in some people, Aβ plaques appear to be latecomers. On the other hand, recent evidence suggests tau proteins are there from the very earliest stages.

In light of all this research, it’s highly likely there are specific subtypes of AD that we simply haven’t teased apart yet. The new research has helped unbraid three major strands. To do this, researchers analysed 1,543 transcriptomes – the genetic processes being express in the cellacross five brain regions, which were collected post mortem from two AD cohorts.

Source: https://advances.sciencemag.org/

Blocking Enzymes Reverse Alzheimer’s Memory Loss

Inhibiting certain enzymes involved in abnormal gene transcription may offer a way to restore memory loss associated with Alzheimer’s disease, a new study in mice suggests.

The findings could pave the way toward new treatments for Alzheimer’s disease (AD).

“By treating AD mouse models with a compound to inhibit these enzymes, we were able to normalize gene expression, restore neuronal function, and ameliorate cognitive impairment,” says senior author Zhen Yan, a professor in the department of physiology and biophysics in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

Alzheimer’s disease alters the expression of genes in the prefrontal cortex, a key region of the brain controlling cognitive processes and executive functions.

When they focused on gene changes caused by epigenetic processes (those not related to changes in DNA sequences) such as aging, the researchers could reverse elevated levels of harmful genes that cause memory deficits in AD.

The current research extends the work the team reported in 2019 in the journal Brain, in which they reversed the loss or downregulation of genes beneficial to cognitive function in AD.

In the new paper in Science Advances, the team reports they reversed the upregulation of genes involved in impairing cognitive function.


Nanoparticle Drug-Delivery To Treat Brain Disorders

In the past few decades, researchers have identified biological pathways leading to neurodegenerative diseases and developed promising molecular agents to target them. However, the translation of these findings into clinically approved treatments has progressed at a much slower rate, in part because of the challenges scientists face in delivering therapeutics across the blood-brain barrier (BBB) and into the brain.

To facilitate successful delivery of therapeutic agents to the brain, a team of bioengineers, physicians, and collaborators at Brigham and Women’s Hospital and Boston Children’s Hospital created a nanoparticle platform, which can facilitate therapeutically effective delivery of encapsulated agents in mice with a physically breached or intact BBB. In a mouse model of traumatic brain injury (TBI), they observed that the delivery system showed three times more accumulation in brain than conventional methods of delivery and was therapeutically effective as well, which could open possibilities for the treatment of numerous neurological disorders.

It’s very difficult to get both small and large molecule therapeutic agents delivered across the BBB,” said corresponding author Nitin Joshi, PhD, an associate bioengineer at the Center for Nanomedicine in the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our solution was to encapsulate therapeutic agents into biocompatible nanoparticles with precisely engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB.”

The technology could enable physicians to treat secondary injuries associated with TBI that can lead to Alzheimer’s, Parkinson’s, and other neurodegenerative diseases, which can develop during ensuing months and years once the BBB has healed.

To be able to deliver agents across the BBB in the absence of inflammation has been somewhat of a holy grail in the field,” said co-senior author Jeff Karp, PhD, of the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.”

Findings were published in Science Advances.


How to Protect Neurons and Encourage Their Growth

Many neurodegenerative conditions, from glaucoma to Alzheimer’s disease, are characterized by injury to axons — the long, slender projections that conduct electrical impulses from one nerve cell to another, facilitating cellular communications. Injury to axons often leads to neuronal impairment and cell death.

Researchers know that inhibiting an enzyme called dual leucine zipper kinase (DLK) appears to robustly protect neurons in a wide range of neurodegenerative diseases models, but DLK also inhibits axonal regeneration. Until now, there have been no effective methods to modify genes to improve both the long-term survival of neurons and promote regeneration.

In a paper published December 14, 2020 in PNAS, a multi-university team led by researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health identified another family of enzymes called germinal cell kinase four kinases (GCK-IV kinases) whose inhibition is robustly neuroprotective, while also permitting axon regeneration, making it an attractive therapeutic approach for treating at some neurodegenerative diseases.

Example of retinal ganglion cells with axons and dendrites in the retina of a healthy eye.

We basically figured out that there are a set of genes that, when inhibited, allow optic nerve cells to survive and regenerate,” said senior author Derek Welsbie, MD, PhD, associate professor of ophthalmology in the Viterbi Family Department of Ophthalmology at Shiley Eye Institute.

Prior to this work, the field knew how to get these cells to survive, but not regenerate. Conversely, there are ways to promote regeneration, but then the survival was rather modest. Of course, for a successful strategy of vision restoration, you need both and this is a step in that direction.”

Source: https://ucsdnews.ucsd.edu/

Human Brain Cells Gene-edited To reduce The Risk Of Developing Alzheimer’s Disease

Cells in the human brain could one day be edited by scientists to prevent the development of Alzheimer’s disease, a new study suggests. The causes of Alzheimer’s are still not well understood, but a leading theory is that it is triggered by the build-up of a protein called beta-amyloid outside the brain cells. Researchers from Laval University in Canada have been investigating how a key gene in human nerve cells could reduce the formation of this protein. Many variants of this gene increases beta-amyloid production, but one variant, called A673T, instead reduces it.

A673T was first discovered in 2012, and is only active in one in 150 people in Scandinavia, but those that have it are four times less likely to get Alzheimer’s. The researchers believe that switching on this gene variant in brain cells could reduce the production of beta-amyloid and thereby reduce Alzheimer’s risk. As the A673T variant doesn’t become relevant until later in life, it isn’t selected for by evolution, according to the study authors. It differs from other variants of the gene by a single DNA letter. Researchers showed that, by editing this one DNA letter, they were able to activate the A673T variant in brain cells growing in a culture dish. Jacques Tremblay and colleagues say this is the first step to proving that engineering the variant into brains could have the same benefits as inheriting it.

The team are still refining the technique before they try it on animals. The researchers initially used a CRISPR technique called base editing, which allows the direct, irreversible conversion of a DNA base into another, targeted base. However, they have now switched to a relatively new method called prime editing – a ‘search and replace‘ technique for editing genomes that directly writes new genetic information into a targeted DNA site using a fusion protein.  Working with cells in a dish they managed to edit about 40 per cent of the cells, but they think a higher proportion might be needed for it to work in a human brain.

The researchers  worked with a process known as base editing, a relatively new method that allows the direct, irreversible conversion of a DNA base into another, targeted base
Source: https://www.dailymail.co.uk/