How to Diagnose Alzheimer’s Through Retina

The onset of Alzheimer’s disease can be diagnosed by examining proteins in the retina instead of complicated and invasive PET scans or cerebrospinal fluid analysis. Alzheimer’s disease – the progressive neurological disorder that causes the brain to shrink and brain cells to die – is the most common cause of dementia. The disease causes a continuous decline in thinking, behavior and social skills that affect a person’s ability to function independently.

But while the disorder is incurable, it is important to diagnose it as rapidly as possible so measures can be taken to slow the decline. Doctors hope to eventually develop treatments to reduce the risk of developing Alzheimer’s disease.

But now, doctors in the ophthalmology department of the Samson Assuta-Ashdod University Hospital suggest a much simpler way to diagnose Alzheimer’s – by looking for beta-amyloid plaques and abnormal tau proteins in the retina of the eye. The advantage is the accessibility of the retina for direct visualization by non-invasive means.

The retina is a component of the central nervous system that can easily be accessed by technology used routinely by ophthalmologists, they wrote. Photoreceptors in this “screen” at the back of the eye absorb light and transfer data to the retinal ganglion cell layer. Axons (long, slender nerve fibers) in this layer accumulate along the retinal nerve fiber layer and transfer the data to the brain via the optic nerve connected to the eye.

Since the retina is connected to the brain, it seems that changes in this part of the eye reflect pathological processes in the brain, the authors wrote, including the development of Alzheimer’s disease. Amyloid-beta plaques have been found in the retina of cadavers in autopsies of people who died of Alzheimer’s.

Turmeric is a natural, intensely yellow-colored spice that attaches itself to plaques of amyloid-beta. Ten Alzheimer’s patients and six healthy controls were asked to swallow turmeric capsules. A few days later, their retinas were examined. The yellow spice was found to stick to the retinal cells in Alzheimer’s patients but not in the healthy controlsOther non-invasive tests of the retina – including optical coherence tomography and optical coherence tomography angiography – were also conducted and found to point to the early development of Alzheimer’s, the authors wrote. Still, larger tests must be conducted with these means before they can be implemented clinically. A clear biomarker must also be found in the individual to be sure the patient is developing Alzheimer’s and sent for treatments, they concluded.

The research, just published in the latest issue of Harefuah – the Hebrew-language journal of the Israel Medical Association – was conducted by Drs. Keren Wood of the Samson Assuta Ashdod Hospital and Ben-Gurion University of the Negev, Idit Maharshak of Wolfson Medical Center in Holon and Tel Aviv University’s Sackler Faculty of Medicine, and Yosef Koronyo and Maya Koranyo-Hamaoui of the Cedars-Sinai Medical Center in Los Angeles, California.


Reprogramming the Brain’s Cleaning Crew to Mop Up Alzheimer’s Disease

The discovery of how to shift damaged brain cells from a diseased state into a healthy one presents a potential new path to treating Alzheimer’s and other forms of dementia, according to a new study from researchers at UC San Francisco (UCSF). The research focuses on microglia, cells that stabilize the brain by clearing out damaged neurons and the protein plaques often associated with dementia and other brain diseases. These cells are understudied, despite the fact that changes in them are known to play a significant role Alzheimer’s and other brain diseases, said Martin Kampmann, PhD, senior author on the study, which appears in Nature Neuroscience.

Microglia (green) derived from human stem cells

Now, using a new CRISPR method we developed, we can uncover how to actually control these microglia, to get them to stop doing toxic things and go back to carrying out their vitally important cleaning jobs,”  Kampmann said. “This capability presents the opportunity for an entirely new type of therapeutic approach.

Most of the genes known to increase the risk for Alzheimer’s disease act through microglial cells. Thus, these cells have a significant impact on how such neurodegenerative diseases play out, said Kampmann. Microglia act as the brain’s immune system. Ordinary immune cells can’t cross the blood-brain barrier, so it’s the task of healthy microglia to clear out waste and toxins, keeping neurons functioning at their best. When microglia start losing their way, the result can be brain inflammation and damage to neurons and the networks they form. Under some conditions, for example, microglia will start removing synapses between neurons. While this is a normal part of brain development in a person’s childhood and adolescent years, it can have disastrous effects in the adult brain.

Over the past five years or so, many studies have observed and profiled these varying microglial states but haven’t been able to characterize the genetics behind them. Kampmann and his team wanted to identify exactly which genes are involved in specific states of microglial activity, and how each of those states are regulated. With that knowledge, they could then flip genes on and off, setting wayward cells back on the right track. Accomplishing that task required surmounting fundamental obstacles that have prevented researchers from controlling gene expression in these cells. For example, microglia are very resistant to the most common CRISPR technique, which involves getting the desired genetic material into the cell by using a virus to deliver it. To overcome this, Kampmann’s team coaxed stem cells donated by human volunteers to become microglia and confirmed that these cells function like their ordinary human counterparts. The team then developed a new platform that combines a form of CRISPR, which enables researchers to turn individual genes on and off – and which Kampmann had a significant hand in developing – with readouts of data that indicate functions and states of individual microglia cells.

Through this analysis, Kampmann and his team pinpointed genes that affect the cell’s ability to survive and proliferate, how actively a cell produces inflammatory substances, and how aggressively a cell prunes synapses. And because the scientists had determined which genes control those activities, they were able to reset the genes and flip the diseased cell to a healthy state.


Nanobody Penetrates Brain Cells to Halt the Progression of Parkinson’s

Researchers from the Johns Hopkins University School of Medicine have helped develop a nanobody capable of getting through the tough exterior of brain cells and untangling misshapen proteins that lead to Parkinson’s disease, Lewy body dementia, and other neurocognitive disorders. The research, published last month in Nature Communications, was led by Xiaobo Mao, an associate professor of neurology at the School of Medicine, and included scientists at the University of Michigan, Ann Arbor. Their aim was to find a new type of treatment that could specifically target the misshapen proteins, called alpha-synuclein, which tend to clump together and gum up the inner workings of brain cells. Emerging evidence has shown that the alpha-synuclein clumps can spread from the gut or nose to the brain, driving the disease progression.

Nanobodies—miniature versions of antibodies, which are proteins in the blood that help the immune system find and attack foreign pathogens—are natural compounds in the blood of animals such as llamas and sharks and are being studied to treat autoimmune diseases and cancer in humans. In theory, antibodies have the potential to zero in on clumping alpha-synuclein proteins, but have a hard time getting through the outer covering of brain cells. To squeeze through these tough brain cell coatings, the researchers decided to use nanobodies instead. The researchers had to shore up the nanobodies to help them keep stable within a brain cell. To do this, they genetically engineered them to rid them of chemical bonds that typically degrade inside a cell. Tests showed that without the bonds, the nanobody remained stable and was still able to bind to misshapen alpha-synuclein.

The team made seven similar types of nanobodies, known as PFFNBs, that could bind to alpha-synuclein clumps. Of the nanobodies they created, onePFFNB2—did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomer of alpha-synuclein, which are not harmful and may have important functions in brain cells. Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from collecting into clumps, but it can disrupt and destabilize the structure of existing clumps.

The structure of alpha-synuclein clumps (left) was disrupted by the nanobody PFFNB2. The debris from the disrupted clump is shown on the right.

Strikingly, we induced PFFNB2 expression in the cortex, and it prevented alpha-synuclein clumps from spreading to the mouse brain’s cortex, the region responsible for cognition, movement, personality, and other high-order processes,” says Ramhari Kumbhar, the co-first author and a postdoctoral fellow at the School of Medicine.

The success of PFFNB2 in binding harmful alpha-synuclein clumps in increasingly complex environments indicates that the nanobody could be key to helping scientists study these diseases and eventually develop new treatments,” Mao says.


Breakthrough Opens New Method to Fight Alzheimer’s

During experiments in animal models, researchers at the University of Kansas (KU)  have discovered a possible new approach to immunization against Alzheimer’s disease (AD). Their method uses a recombinant methionine (Met)-rich protein derived from corn that was then oxidized in vitro to produce the antigen: methionine sulfoxide (MetO)-rich protein. This antigen, when injected to the body, goads the immune system into producing antibodies against the MetO component of beta-amyloid, a protein that is toxic to brain cells and seen as a hallmark of Alzheimer’s disease.

As we age, we have more oxidative stress, and then beta-amyloid and other proteins accumulate and become oxidized and aggregated – these proteins are resistant to degradation or removal,” said lead researcher Jackob Moskovitz, associate professor of pharmacology & toxicology at the KU School of Pharmacy. “In a previous 2011 published study, I injected mouse models of Alzheimer’s disease with a similar methionine sulfoxide-rich protein and showed about 30% reduction of amyloid plaque burden in the hippocampus, the main region where damage from Alzheimer’s disease occurs.”

The MetO-rich protein used by Moskovitz for the vaccination of AD-model mice is able to prompt the immune system to produce antibodies against MetO-containing proteins, including MetO-harboring beta-amyloid. The introduction of the corn-based MetO-rich protein (antigen) fosters the body’s immune system to produce and deploy the antibodies against MetO to previously tolerated MetO-containing proteins (including MetO-beta-amyloid), and ultimately reduce the levels of toxic forms of beta-amyloid and other possible proteins in brain.

According to Moskovitz, there was a roughly 50% improvement in the memory of mice injected with the methionine sulfoxide (MetO)-rich protein versus the control.

The findings have been just published in the peer-reviewed open-access journal Antioxidants.


How to Control Neurons in the Brain

Researchers out of San Diego’s Salk Institute have gotten mice to move their limbs by stimulating brain cells using ultrasound. When mice were engineered to have their brain cells produce a special protein, the researchers found that hitting them with ultrasoundturned on” the cells, causing small, but perceptible, movements in their limbs. The technique, called “sonogenetics,” is the latest in a line of methods that look to stimulate and alter neurons directly, without using drugs.

We’ve spent so much time over the last few decades focusing on pharmacologic therapies,” said Colleen Hanlon, a biologist at Wake Forest not involved with the study. “This paper is another really important piece to this puzzle of developing neural circuit-based therapeutics for disease.”

 Sonogenetics is just one of the ways researchers have begun controlling neurons in the brain, turning them off or on at will. Perhaps the most well-known method is using electrical stimulation. In deep brain stimulation, researchers surgically implant electrodes into specific areas of the brain. When these electrodes fire off at the right time and with the right frequency, they can make tremors disappear, improve memory, and even treat depression.

Taking a step up on the wildness scale, scientists can also activate, or turn off, neurons using light, a technique called optogenetics. Optogenetics works by genetically engineering brain cells to produce light-sensitive proteins, which can be hit with a laser, causing the neuron to fire or not. A similar mechanism is behind sonogenetics, except the protein reacts to ultrasound. Ultrasound is appealing because of its well-understood safety profile and the fact that it is already used to target locations deep within the body. “Ultrasound is safe, noninvasive, and can be easily focused through thin bone and tissue to volumes of a few cubic millimeters,” the researchers wrote in their study, published in Nature Communications.

In optogenetics, by contrast, because skin and bone are opaque, even powerful lights will have a hard time reaching neurons deeper than the outer layer of the brain. Salk neuroscientist Sreekanth Chalasani and his colleagues pioneered sonogenetics several years ago in a tiny worm called a nematode. In the worms, they used an ultrasound-reacting protein called TRP-4. But when they put it into mammalian cells, well … nada. And thus began a six-year quest to find an ultrasound-reactive protein that works in mammals. They found it — a protein called TRPA1. The researchers first tested the protein in mouse neurons in the lab. When those cells reacted to ultrasound by producing electrical signals, they engineered it into living mice. When the TRPA1-producing mice were exposed to ultrasound, electrical signals coursed through their limbs — and a little bit of movement, too.

It’s a very exciting contribution and an important step,” adds Caltech sonogenetics researcher Mikhail Shapiro, who was uninvolved with the work.  “This is one of the papers that’s come out over the last several years that shows that it’s a real possibility that you can use ultrasound to directly modulate the activity of specific neurons.”


Could Sound Replace Pacemakers and Insulin Pumps?

Imagine a future in which crippling epileptic seizures, faltering hearts and diabetes could all be treated not with scalpels, stitches and syringes, but with sound. Though it may seem the stuff of science fiction, a new study shows that this has solid real-world potential.

Sonogenetics – the use of ultrasound to non-invasively manipulate neurons and other cells – is a nascent field of study that remains obscure amongst non-specialists, but if it proves successful it could herald a new era in medicine.

In the new study published in Nature Communications, researchers from the Salk Institute for Biological Studies in California, US, describe a significant leap forward for the field, documenting their success in engineering mammalian cells to be activated using ultrasound. The team say their method, which they used to activate human cells in a dish and brain cells inside living mice, paves the way toward non-invasive versions of deep brain stimulation, pacemakers and insulin pumps.

Going wireless is the future for just about everything,” says senior author Dr Sreekanth Chalasani, an associate professor in Salk’s Molecular Neurobiology Laboratory. “We already know that ultrasound is safe, and that it can go through bone, muscle and other tissues, making it the ultimate tool for manipulating cells deep in the body.

Chalasani is the mastermind who first established the field of sonogenetics a decade ago. He discovered that ultrasound sound waves beyond the range of human hearing — can be harnessed to control cells. Since sound is a form of mechanical energy, he surmised that if brain cells could be made mechanically sensitive, then they could be modified with ultrasound.

In 2015 his research group provided the first successful demonstration of the theory, adding a protein to cells of a roundworm, Caenorhabditis elegans, that made them sensitive to low-frequency ultrasound and thus enabled them to be activated at the behest of researchers.

Chalasani and his colleagues set out to search for a new protein that would work in mammals. Although a few proteins were already known to be ultrasound sensitive, no existing candidates were sensitive at the clinically safe frequency of 7MHz – so this was where the team set their sights. To test whether TRPA1 protein could activate cell types of clinical interest in response to ultrasound, the team used a gene therapy approach to add the genes for human TRPA1 to a specific group of neurons in the brains of living mice. When they then administered ultrasound to the mice, only the neurons with the TRPA1 genes were activated.

Clinicians treating conditions including Parkinson’s disease and epilepsy currently use deep brain stimulation, which involves surgically implanting electrodes in the brain, to activate certain subsets of neurons. Chalasani says that sonogenetics could one day replace this approach—the next step would be developing a gene therapy delivery method that can cross the blood-brain barrier, something that is already being studied. Perhaps sooner, he says, sonogenetics could be used to activate cells in the heart, as a kind of pacemaker that requires no implantation.


How to Fires Up our Synapses

Processing of sensory impressions and information depends very much on how the synapses in our brain work. A team around chemist Robert Ahrends from the University of Vienna and neuroscientist Michael R. Kreutz from Leibniz Institute for Neurobiology in Magdeburg now showed how lipid and protein regulation impact brain’s processing of a beautiful and stimulating environment. The lipids located in the membranes of the synapses are central to signal transmission, the researchers report in “Cell Reports“.

“We usually enjoy a beautiful environment, socializing, a cosy apartment, good restaurants, a park – all this inspires us,” says Robert Ahrends from the Institute of Analytical Chemistry of the University of Vienna and former group leader at ISAS in Dortmund. Previous studies have already shown that such an enriched environment can sometimes have a positive effect on child development or even on the human ability to regenerate, e.g. after a stroke, however the reason for these observations “was not yet clarified at the molecular level“.

Stimulating sensory perceptions are ultimately formed via the activity or regulation of synapses, i.e. those connecting units between our neurons that transfer information from one nerve cell to another. To clarify the underlying molecular principles, the researchers offered the rodents, their model organisms, an enriched environment based on plenty of room to move, a running wheel and other toys.

With the help of post-genomic analysis strategies (multiomics) and using state-of-the-art mass spectrometry and microscopy as well as bioinformatics for data analysis, they investigated the regulation of synapses in the hippocampus of the rodents, more precisely the interaction of the proteins and especially lipids (fats) located in the synaptic membranes.

80 percent of the brain cells are only supporting cells. We have therefore focused on the synapses as central sites of signal transmission and isolated them,” says neuroscientist Michael Kreutz. The team gathered quantitative and qualitative information about the network of molecules regulated at synapses and examined their lipid metabolism, also under the influence of an enriched environment.
The analyses revealed that 178 proteins and 20 lipids were significantly regulated depending on whether the rodents had spent time in an enriched environment or an uncomfortable one.


Toxic Fatty Acids Play a Critical Role in Brain Cell Death

Rodent studies led by researchers at NYU Grossman School of Medicine have found that cells called astrocytes, which normally nourish neurons, also release toxic fatty acids after neurons are damaged. The team suggests that this phenomenon is likely the driving factor behind most, if not all, diseases that affect brain function, as well as the natural breakdown of brain cells seen in aging.

Our findings show that the toxic fatty acids produced by astrocytes play a critical role in brain cell death and provide a promising new target for treating, and perhaps even preventing, many neurodegenerative diseases,” said Shane Liddelow, PhD, who is co-senior and corresponding author of the researchers’ published paper in Nature. In their report, which is titled, “Neurotoxic reactive astrocytes induce cell death via saturated lipids,” the team concluded. “The findings highlight the important role of the astrocyte reactivity response in CNS injury and neurodegenerative disease and the relatively unexplored role of lipids in CNS signaling.”


Astrocytes—star-shaped glial cells of the central nervous system (CNS)—undergo functional changes in response to CNS disease and injury, but the mechanisms that underlie these changes and their therapeutic relevance remain unclear, the authors noted. Interestingly, previous research has pointed to astrocytes as the culprits behind cell death seen in Parkinson’s disease and dementia, among other neurodegenerative diseases. “Astrocytes regulate the response of the central nervous system to disease and injury, and have been hypothesized to actively kill neurons in neurodegenerative disease,” the researchers stated. But while many experts believed that these cells release a neuron-killing molecule to clear away damaged brain cells, the identity of the toxin has remained a mystery.

The studies by Liddelow and colleagues now provide what they say is the first evidence that tissue damage prompts astrocytes to produce two kinds of fats, long-chain saturated free fatty acids and phosphatidylcholines. These fats then trigger cell death in damaged neurons. For their investigation, researchers analyzed the molecules released by astrocytes collected from rodents. “Previous evidence suggested that the toxic activity of reactive astrocytes is mediated by a secreted protein, so we first sought to identify the toxic agent by protein mass spectrometry of reactive versus control astrocyte conditioned medium (ACM),” they wrote.


Internet Of Thoughts

Imagine a future technology that would provide instant access to the world’s knowledge and artificial intelligence, simply by thinking about a specific topic or question. Communications, education, work, and the world as we know it would be transformed. Writing in Frontiers in Neuroscience, an international collaboration led by researchers at UC Berkeley and the US Institute for Molecular Manufacturing predicts that exponential progress in nanotechnology, nanomedicine, AI, and computation will lead this century to the development of a “Human Brain/Cloud Interface” (B/CI), that connects neurons and synapses in the brain to vast cloud-computing networks in real time.

The B/CI concept was initially proposed by futurist-author-inventor Ray Kurzweil, who suggested that neural nanorobots – brainchild of Robert Freitas, Jr., senior author of the research – could be used to connect the neocortex of the human brain to a “synthetic neocortex” in  . Our wrinkled neocortex is the newest, smartest, ‘conscious’ part of the brain. Freitas’ proposed neural nanorobots would provide direct, real-time monitoring and control of signals to and from brain cells.

These devices would navigate the human vasculature, cross the blood-brain barrier, and precisely autoposition themselves among, or even within brain cells,” explains Freitas. “They would then wirelessly transmit encoded information to and from a cloud-based supercomputer network for real-time brain-state monitoring and data extraction.

This cortex in the cloud would allow “Matrix“-style downloading of information to the brain, the group claims. “A human B/CI system mediated by neuralnanorobotics could empower individuals with instantaneous access to all cumulative human knowledge available in the cloud, while significantly improving human learning capacities and intelligence,” says lead author Dr. Nuno Martins.

B/CI technology might also allow us to create a future “global superbrain” that would connect networks of individual human brains and AIs to enable collective thought. “While not yet particularly sophisticated, an experimental human ‘BrainNet’ system has already been tested, enabling thought-driven information exchange via the cloud between individual brains,” explains Martins. “It used electrical signals recorded through the skull of ‘senders’ and magnetic stimulation through the skull of ‘receivers,’ allowing for performing cooperative tasks. With the advance of neuralnanorobotics, we envisage the future creation of ‘superbrains’ that can harness the thoughts and thinking power of any number of humans and machines in real time. This shared cognition could revolutionize democracy, enhance empathy, and ultimately unite culturally diverse groups into a truly global society.”

According to the group’s estimates, even existing supercomputers have processing speeds capable of handling the necessary volumes of neural data for B/CI – and they’re getting faster, fast. Rather, transferring neural data to and from supercomputers in the cloud is likely to be the ultimate bottleneck in B/CI development. “This challenge includes not only finding the bandwidth for global data transmission,” cautions Martins, “but also, how to enable data exchange with neurons via tiny devices embedded deep in the brain.”

One solution proposed by the authors is the use of ‘magnetoelectric nanoparticles‘ to effectively amplify communication between neurons and the cloud. “These nanoparticles have been used already in living mice to couple external magnetic fields to neuronal electric fields – that is, to detect and locally amplify these magnetic signals and so allow them to alter the electrical activity of neurons,” explains Martins. “This could work in reverse, too: electrical signals produced by neurons and nanorobots could be amplified via magnetoelectric nanoparticles, to allow their detection outside of the skull.” Getting these nanoparticles – and nanorobots – safely into the brain via the circulation, would be perhaps the greatest challenge of all in B/CI.

A detailed analysis of the biodistribution and biocompatibility of nanoparticles is required before they can be considered for human development. Nevertheless, with these and other promising technologies for B/CI developing at an ever-increasing rate, an ‘internet of thoughts’ could become a reality before the turn of the century,” Martins concludes.