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.

Source: https://www.ucsf.edu/

Dementia Test on IPad

A dementia diagnosis usually starts with a family member noticing that something isn’t quite right: a partner becoming forgetful, a normally placid parent losing their temper more often. From there, there are doctor’s appointments—memory and behavior tests that haven’t changed in years, brain scans if the money is there, or one of the battery of new blood tests looking for the biomarkers of brain damage. And then: nothing.

Neurodegenerative diseases like dementia and Alzheimer’s are more feared than cancer and heart disease combined, according to a 2016 survey, and one of the most frightening things about them is how little we still know. There are no cures, and few effective treatments.

So you might question the benefits of a 5-minute test that can assess your risk of getting dementia before you show any symptoms. The Integrated Cognitive Assessment (ICA) test, developed by the British startup Cognetivity Neurosciences, has been granted Food and Drug Administration clearance to be marketed in the United States and is being trialled at several NHS trusts in the UK. But is there any point in taking a test for a disease you can’t do anything about?

The ICA is designed as a “semi-supervisedscreening test, says Cognetivity CEO Sina Habibi. It could form part of an annual health check-up for the over-50s, looking for the earliest signs of neurodegenerative disease before they become apparent in behavior.In the same way you look at blood pressure, you could look at the brain with a cognitive test to see if there’s something malfunctioning,” he says.

An early diagnosis could help people plan ahead and put their affairs in order—but arguably that’s something they should probably be doing anyway. Lifestyle tweaks such as eating less fat, exercising more, or drinking less can also reduce risk, particularly in vascular dementia, which is caused by poor blood supply to the brain and is therefore closely linked to heart health.

The procedure runs on an iPad. A zebra appears onscreen and then disappears, replaced by a railway bridge. There are flashes of beach scenes in black and white, and then a glimpse of an exotic bird, all interspersed with monochrome grids and fuzzy static—a captcha at warp speed. The user’s task is simple: They tap on the right side of the screen whenever they see an animal in one of the pictures, and on the left side when they don’t.

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.

https://www.eurekalert.org/

Bringing drugs to the brain to treat neurodegenerative diseases

The blood-brain barrier is the main obstacle in treating neurodegenerative diseases such as Alzheimer and Parkinson. According to a recent study conducted by Jean-Michel Rabanel, a postdoctoral researcher under the supervision of Professor Charles Ramassamy, nanoparticles with specific properties could cross this barrier and be captured by neuronal cells. Researchers are confident that these results will open important prospects for releasing drugs directly to the brain. This breakthrough finding would enable improved treatment for neurodegenerative diseases affecting more than 565,000 Canadians, including 141,000 Quebecers.

The blood-brain barrier filters out harmful substances to prevent them from freely reaching the brain. But this same barrier also blocks the passage of drugs,” explains the pharmacologist Charles Ramassamy. Typically, high doses are required to get a small amount of the drug into the brain. What remains in the bloodstream has significant side effects. Often, this discomfort leads the patient to stop the treatment.  The use of nanoparticles, which encapsulate the drugs, would result in fewer collateral side effects while increasing brain efficiency.

To prove the effectiveness of this method, the research team first tested it on cultured cells, then on zebrafish. “This species offers several advantages. Its blood-brain barrier is similar to that of humans and its transparent skin makes it possible to see nanoparticles’ distribution almost in real time,” says Professor Ramassamy, Chairholder of the Louise and André Charron Research Chair on Alzheimer’s disease, from the Fondation Armand-Frappier.

Using in vivo tests, researchers were able to observe the crossing of the blood-brain barrier. They also confirmed the absence of toxicity in the library of selected nanoparticles. “We made the particles with polylactic acid (PLA), a biocompatible material that is easily eliminated by the body. A layer of polyethylene glycol (PEG) covers these nanoparticles and makes them invisible to the immune system, so they can longer circulate in the bloodstream,” he explains.

The findings have been published in the Journal of Controlled Release.

http://www.inrs.ca

Biomarker detects Alzheimer’s decades before symptoms appear

Two new studies, published in the journal The Lancet Neurology, are suggesting increasing levels of a particular brain protein, detected in blood and spinal fluid, could be the earliest sign of neurodegenerative diseases such as Alzheimer’s and Huntington’sNeurofilament light chain (NfL) is a protein that is released as a result of brain cell damage. It is one of the most promising early-stage biomarkers for a variety of neurodegenerative diseases, including Parkinson’s disease, ALS and multiple sclerosis.

It is commonly suspected that the neurodegeneration associated with many of these devastating diseases begins years, or even decades, before clinical symptoms finally appear. And on the back of many failed drug trials, researchers are beginning to believe that once symptoms eventually appear much of the neurological damage could be irreversible. So finding ways to catch these diseases at the earliest possible point will be vital in delivering effective treatments.

Huntington’s disease is a heritable neurodegenerative disease with no cure. Clinical symptoms can begin appearing at any age, however, generally the condition doesn’t become apparent until middle-age, and once symptoms do appear a gradual decline to death takes place over about 20 years. Researchers have homed in on a number of clues, both behavioral and physiological, to detect the earliest stages of the disease but a new study from an international team of researchers is suggesting NfL levels in cerebrospinal fluid (CSF) could detect Huntington’s neurodegeneration up to 24 years before the clinical onset of the disease.

Other studies have found that subtle cognitive, motor and neuropsychiatric impairments can appear 10-15 years before disease onset,” explains co-first author on the study, Rachael Scahill. “We suspect that initiating treatment even earlier, just before any changes begin in the brain, could be ideal, but there may be a complex trade-off between the benefits of slowing the disease at that point and any negative effects of long-term treatment.

The new study presents the most detailed investigation ever conducted into early-stage Huntington’s disease biomarkers in a young cohort of patients. The study recruited 64 subjects, all carrying the Huntington’s gene mutation, and all estimated to be an average of 24 years ahead of the disease onset. The cohort was subjected to a large assortment of tests, with the researchers searching for an early sign of the disease. Elevated CSF NfL levels, compared to a control group, turned out to be the most prominent early sign of the disease. The researchers suggest this is the earliest sign of neuronal damage related to Huntington’s disease ever detected, and offers scientists a new biomarker to use to recruit subjects for clinical trials testing new preventative treatments.

We have found what could be the earliest Huntington’s-related changes, in a measure which could be used to monitor and gauge effectiveness of future treatments in gene carriers without symptoms,” says co-first author Paul Zeun. In the Huntington’s study it was primarily NfL levels in spinal fluid that presented as the most effective early diagnostic biomarker of the disease. However, another new study examining NfL levels in relation to Alzheimer’s disease, is suggesting a more simple blood test could be useful in detecting NfL changes for that particular neurodegenerative disease.

A study published early in 2019 suggested increasing NfL levels in blood samples could detect Alzheimer’s disease around a decade before clinical symptoms appear. Yakeel Quiroz, from Harvard Medical School, wondered how early this biomarker could indicate the neurodegenerative disease.

We wanted to determine the earliest age at which plasma NfL levels could distinguish individuals at high risk of Alzheimer’s,” says Quiroz, co-first author on the study.

The researchers examined more than 1,000 subjects with a particular familial genetic mutation that makes them at a high risk of developing Alzheimer’s disease. The cohort was aged between eight and 75 years, and the results remarkably revealed increasing NfL levels could be detected at the early age of 22. The estimated median age of onset for mild cognitive impairment associated with this form of familial Alzheimer’s disease is 44, so the researchers say the biomarker could indicate the very earliest stage of neurodegeneration linked to the disease, 22 years before symptoms appear.

Source: https://newatlas.com/