Potential treatment for Alzheimer’s dementia using cell therapy

Researchers from Gladstone Institute uncovered the therapeutic benefits of genetically improving interneurons with a voltage-gated sodium channel Nav1.1 and transplanting them into the brain of a mouse model of Alzheimer’s disease. This study is led by Jorge Palop, Ph.D., an assistant investigator at the Gladstone Institutes. The study findings are published in journal Neuron.

Inhibitory interneurons are essential for managing brain rhythms.  They regulate the oscillatory rhythms and network synchrony that are required for cognitive functions. Network dysrhythmias in Alzheimer’s disease and multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons in Alzheimer’s disease (AD).

Researchers found a way to re-engineer inhibitory interneurons genetically boosted by adding protein Nav1.1 to improve their function. They showed that these enhanced interneurons, when transplanted into the abnormal brain of Alzheimer mice, can properly control the activity of excitatory cells and restore brain rhythms.

The researchers then discovered that the interneurons with enhanced function were able to overcome the toxic disease environment and restore brain function. The findings could eventually lead to the development of new treatment options for patients with Alzheimer’s disease.

In addition to examining if the cell therapy could be translated from mice to humans, researchers are working on pharmaceutical drugs to enhance the function of inhibitory interneurons.

Citation: Martinez-Losa, Magdalena, Tara E. Tracy, Keran Ma, Laure Verret, Alexandra Clemente-Perez, Abdullah S. Khan, Inma Cobos, Kaitlyn Ho, Li Gan, Lennart Mucke, Manuel Alvarez-Dolado, and Jorge J. Palop. “Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer’s Disease.” Neuron, 2018. doi:10.1016/j.neuron.2018.02.029.

Research funding: National Institutes of Health, Alzheimer’s Association; S.D. Bechtel, Jr. Foundation.

Adapted from press release by Gladstone Institutes.

New biomarkers for assessing Alzheimers dementia risk and early diagnosis

Researchers from the University of Texas have analyzed biomarkers to predict future risk of dementia. Their findings are published in journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 

Dementia is a rising tidal wave of devastation for families and society. Age is the biggest risk factor. Alzheimer’s disease, which is the leading cause of dementia, is the sixth-leading cause of death in the United States, and more than 5 million Americans are currently living with Alzheimer’s. That figure is expected to triple by 2050.

Researchers analyzed metabolites in blood samples taken from 22,623 individuals, including 995 who went on to develop dementia. The participants were enrolled in eight research cohorts in five countries. They found that higher blood concentrations of branched-chain amino acids were associated with lower risk of future dementia. Another molecule, creatinine, and two very low-density lipoprotein (VLDL)specific lipoprotein lipid subclasses also were associated with lower risk of dementia. On the other hand, one high-density lipoprotein (HDL) and one VLDL lipoprotein subclass were associated with increased dementia risk.

These findings will broaden the search for drug targets in dementia caused by Alzheimer’s disease, vascular disease, and other subtypes, said Dr. Seshadri, professor of neurology at UT Health San Antonio. “It is now recognized that we need to look beyond the traditionally studied amyloid and tau pathways and understand the entire spectrum of pathology involved in persons who present with symptoms of Alzheimer’s disease and other dementias,” Dr. Seshadri said. “It is exciting to find new biomarkers that can help us identify persons who are at the highest risk of dementia.”

The study was in persons of European ancestry and was carried out in collaboration with researchers in Finland, the Netherlands, the United Kingdom and Estonia. Dr. Seshadri is eager to replicate it in South Texas. “The Glenn Biggs Institute at UT Health San Antonio will expand these studies to include the diverse racial and ethnic groups who live in South Texas,” she said.

Researchers feel that more studies are needed to clarify whether the branched-chain amino acids and other molecules play a causal role in the dementia disease process or are merely early markers of the disease.

Citation: Tynkkynen, Juho, Vincent Chouraki, Sven J. Van Der Lee, Jussi Hernesniemi, Qiong Yang, Shuo Li, Alexa Beiser, Martin G. Larson, Katri Sääksjärvi, Martin J. Shipley, Archana Singh-Manoux, Robert E. Gerszten, Thomas J. Wang, Aki S. Havulinna, Peter Würtz, Krista Fischer, Ayse Demirkan, M. Arfan Ikram, Najaf Amin, Terho Lehtimäki, Mika Kähönen, Markus Perola, Andres Metspalu, Antti J. Kangas, Pasi Soininen, Mika Ala-Korpela, Ramachandran S. Vasan, Mika Kivimäki, Cornelia M. Van Duijn, Sudha Seshadri, and Veikko Salomaa. “Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimers disease: A prospective study in eight cohorts.” Alzheimers & Dementia, 2018. doi:10.1016/j.jalz.2018.01.003.

Adapted from press release by the University of Texas Health Science Center at San Antonio.

Research finds that gene therapy could be used in early Alzheimers disease in animal studies

Researchers have prevented the development of Alzheimer’s disease in mice by using a virus to deliver a specific gene into the brain.The early-stage findings, by scientists from Imperial College London, open avenues for potential new treatments for the disease. In the study, published in the journal Proceedings of the National Academy of Sciences, the team used a type of modified virus to deliver a gene to brain cells.

The research was funded by Alzheimer’s Research UK and the European Research Council.
Previous studies by the same team suggest this gene, called PGC1 – alpha, may prevent the formation of a protein called amyloid-beta peptide in cells in the lab.

Amyloid-beta peptide is the main component of amyloid plaques, the sticky clumps of protein found in the brains of people with Alzheimer’s disease. These plaques are thought to trigger the death of brain cells.

Alzheimer’s disease affects around 520,000 people in the UK. Symptoms include memory loss, confusion, and change in mood or personality. Worldwide 47.5 million people are affected by dementia – of which Alzheimer’s is the most common form.

There is no cure, although current drugs can help treat the symptoms of the disease. Dr Magdalena Sastre, senior author of the research from the Department of Medicine at Imperial, hopes the new findings may one day provide a method of preventing the disease, or halting it in the early stages.
She explained: “Although these findings are very early they suggest this gene therapy may have potential therapeutic use for patients. There are many hurdles to overcome, and at the moment the only way to deliver the gene is via an injection directly into the brain. However this proof of concept study shows this approach warrants further investigation.”

The modified virus used in the experiments was called a lentivirus vector, and is commonly used in gene therapy explained Professor Nicholas Mazarakis, co-author of the study from the Department of Medicine: “Scientists harness the way lentivirus infects cells to produce a modified version of the virus, that delivers genes into specific cells. It is being used in experiments to treat a range of conditions from arthritis to cancer. We have previously successfully used the lentivirus vector in clinical trials to deliver genes into the brains of Parkinson’s disease patients.”




Image 1 shows brain cells from a mouse cortex that didn’t receive the gene therapy. The amyloid plaques are shown in green, and the glial cells, which surround the plaques, are shown in red (microglia) and magenta (astrocytes). Image 2 shows a mouse cortex that received the gene therapy, and so had fewer amyloid plaques.

In the new study, the team injected the virus, containing the gene PGC-1 – alpha, into two areas of the brain in mice susceptible to Alzheimer’s disease. The areas targeted were the hippocampus and the cortex, as these are the first regions to develop amyloid plaques in Alzheimer’s disease. Damage to the hippocampus affects short-term memory, and leads to a person forgetting recent events, such as a conversation or what they ate for breakfast. The hippocampus is also responsible for orientation, and damage results in a person becoming lost on familiar journeys, such as driving home from the shops.

The cortex, meanwhile, is responsible for long-term memory, reasoning, thinking and mood. Damage can trigger symptoms such as depression, struggling to work out how much money to give at a checkout, how to get dressed or how to cook a familiar recipe.

The animals were treated at the early stages of Alzheimer’s disease, when they still had not developed amyloid plaques. After four months, the team found that mice who received the gene had very few amyloid plaques, compared with the untreated mice, who had multiple plaques in their brain.

Furthermore, the treated mice performed as well in memory tasks as healthy mice. The tasks included challenges such as replacing a familiar object in the mouse’s cage with a new one. If the mice had a healthy memory, they would explore the new object for longer.

The team also discovered there was no loss of brain cells in the hippocampus of the mice who received the gene treatment. In addition to this, the treated mice had a reduction in the number of glial cells, which in Alzheimer’s disease can release toxic inflammatory substances that cause further cell damage.

The protein PGC-1 – alpha, which is coded by the gene, is involved in metabolic processes in the body, including regulation of sugar and fat metabolism. Dr Sastre added that other studies from different institutions suggest physical exercise and the compound resveratrol, found in red wine, may increase levels of PGC-1 – alpha protein. However, resveratrol has only been found to have benefits as a pill, rather than in wine, as the alcohol counteracts any benefit.

The team suggest injections of the gene would be most beneficial in the early stages of the disease, when the first symptoms appear.They now hope to explore translating their findings into human treatments, said Dr Sastre. “We are still years from using this in the clinic. However, in a disease that urgently needs new options for patients, this work provides hope for future therapies.”

Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said: “There are currently no treatments able to halt the progression of damage in Alzheimer’s, so studies like this are important for highlighting new and innovative approaches to take us towards that goal. This research sets a foundation for exploring gene therapy as a treatment strategy for Alzheimer’s disease, but further studies are needed to establish whether gene therapy would be safe, effective and practical to use in people with the disease. The findings support PGC-1-alpha as a potential target for the development of new medicines, which is a promising step on the road towards developing treatments for this devastating condition.”

Adapted from press release by Imperial College of London

Study demonstrates role of gut bacteria in neurodegenerative diseases

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. In more than 90 percent of cases, physicians and scientists do not know what causes these processes to occur.

Robert P. Friedland, M.D., the Mason C. and Mary D. Rudd Endowed Chair and Professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS. This research is published online Oct. 6 in Scientific Reports, a journal of the Nature Publishing Group.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by The Michael J. Fox Foundation, involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, Ph.D., of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

This work supports recent studies indicating that the microbiota may have a role in disease processes in age-related brain degenerations. It is part of Friedland’s ongoing research on the relationship between the microbiota and age-related brain disorders, which involves collaborations with researchers in Ireland and Japan.

“We are pursuing studies in humans and animals to further evaluate the mechanisms of the effects we have observed and are exploring the potential for the development of preventive and therapeutic strategies,” Friedland said.

Publication: Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans.
doi:10.1038/srep34477
Study demonstrates role of gut bacteria in neurodegenerative diseases