New gene delivery vehicle shows promise for human brain gene therapy

 In an important step toward more effective gene therapies for brain diseases, researchers from the Broad Institute of MIT and Harvard have engineered a gene-delivery vehicle that uses a human protein to efficiently cross the blood-brain barrier and deliver a disease-relevant gene to the brain in mice expressing the human protein. Because the vehicle binds to a well-studied protein in the blood-brain barrier, the scientists say it has a good chance at working in patients.

Gene therapy could potentially treat a range of severe genetic brain disorders, which currently have no cures and few treatment options. But FDA-approved forms of the most commonly used vehicle for packaging and delivering these therapies to target cells, adeno-associated viruses (AAVs), aren't able to efficiently cross the blood-brain barrier at high levels and deliver therapeutic cargo. The enormous challenge of getting therapies past this barrier -- a highly selective membrane separating the blood from the brain -- has stymied the development of safer and more effective gene therapies for brain diseases for decades.

Now researchers in the lab of Ben Deverman, an institute scientist and senior director of vector engineering at the Broad, have engineered the first published AAV that targets a human protein to reach the brain in humanized mice. The AAV binds to the human transferrin receptor, which is highly expressed in the blood-brain barrier in humans. In a new study published in Science, the team showed that their AAV, when injected into the bloodstream in mice expressing a humanized transferrin receptor, crossed into the brain at much higher levels than the AAV that is used in an FDA-approved gene therapy for the central nervous system, AAV9. It also reached a large fraction of important types of brain cells, including neurons and astrocytes. The researchers then showed that their AAV could deliver copies of the GBA1 gene, which has been linked to Gaucher's disease, Lewy body dementia, and Parkinson's disease, to a large fraction of cells throughout the brain.

The scientists add that their new AAV could be a better option for treating neurodevelopmental disorders caused by mutations in a single gene such as Rett syndrome or SHANK3 deficiency; lysosomal storage diseases like GBA1deficiency; and neurodegenerative diseases such as Huntington's disease, prion disease, Friedreich's ataxia, and single-gene forms of ALS and Parkinson's disease.

Source: ScienceDaily

Research sheds light on how proteins linked to Alzheimer's disease influence neuronal growth

 New research has shed light in the complex interplay between cell proteins, and how they impact on neurons in neurodevelopmental disorders and Alzheimer's disease.

A new study led by the University of Exeter and published in Royal Society Open Biology has discovered the key role that the protein Contactin-4 (encoded by the gene CNTN4) plays in shaping neurons.

The researchers began studying CNTN4 because it was known to have a role in autism, but its functional roles were not well understood. The team explored how CNTN4 functions within the brain, particularly its interactions with proteins involved in neurodegenerative diseases like Alzheimer's disease.

For the first time, the researchers studied mice who have had the CNTN4 gene knocked out in the cortex, the region of the brain responsible for key functions including memory, thinking and reasoning. They found that neurons developed in a different way in the cortex region.

Researchers have demonstrated for the first time in human cells the interaction between genes CNTN4 and APP, a gene strongly linked to Alzheimer's disease, revealing a co-dependent relationship that is essential for brain development, and specifically for the healthy growth of neurons. They found that CNTN4 not only contributes to neural elongation in the frontal cortex region of the brain, but also CNTN4 expression is regulated via a relationship with APP.

Using studies in genetically modified human cells, the team also discovered that a complex interaction exists between CNTN4 and APP. If CNTN4 is knocked out, then levels of APP decrease, but not to zero. The scientists believe that APP may compensate for the loss of CNTN4, and vice versa.

The study's lead author, Dr Rosemary Bamford, of the University of Exeter Medical School, said: "It was quite remarkable to discover that CNTN4, a gene linked to developmental processes, also plays a role in modulating factors involved in Alzheimer's disease. This intersection of developmental and neurodegenerative pathways offers exciting new insights into the broader implications of these proteins."

Source: ScienceDaily

Genes driving age-related blood cell mutations uncovered

 New research identifies a larger pool of genes involved in clonal haematopoiesis than previously thought, and their implications for disease and diagnostic tests.

Scientists have discovered 17 additional genes that drive the abnormal overgrowth of mutated blood cells as we age. The findings, published in Nature Genetics, provide a more complete view of the genetic factors behind clonal haematopoiesis -- a process associated with aging and linked to increased risks of blood cancers.

Researchers from the Wellcome Sanger Institute, Calico Life Sciences, California, and the University of Cambridge analysed sequencing data from over 200,000 individuals in the UK Biobank cohort. They searched for genes showing signals of "positive selection" -- where mutations allow mutant cell populations to greatly expand over time.

The 17 newly discovered genes were found to have similar disease associations as previously known clonal haematopoiesis mutations, highlighting their clinical significance in driving the accumulation of mutant blood cell clones.

By uncovering these previously unrecognised genetic drivers, the research opens new avenues for studying the molecular mechanisms underlying clonal haematopoiesis and its role in disease development, leading to new ways to promote healthier aging. Additionally, it could lead to better genetic tests that help identify the risks of blood cancers and cardiovascular diseases.

As we age, our cells accumulate random genetic mutations. Some of these mutations can provide a competitive growth advantage, allowing mutant cells to multiply and outnumber the healthy cells, forming large 'clones' or populations of identical mutant cells. When this positive selection happens in blood stem cells, it is called clonal haematopoiesis. This process is associated with blood cancers, cardiovascular disease and other age-related diseases.

While previous studies have identified around 70 genes linked to clonal haematopoiesis, most cases observed recently have not involved mutations in any of these known driver genes. This suggests the involvement of additional genetic factors.

Source: ScienceDaily

Alzheimer's disease without symptoms: How is that possible?

 Everyone experiences aging in their own way, and factors such as genetics, lifestyle and environment play a role in this process. Some individuals reach the age of 90 or even 100 in good health, without medications or brain disease. But how do these individuals maintain their health as they age?

Luuk de Vries from Joost Verhaagen's group, and his colleagues Dick Swaab and Inge Huitinga, looked at brains from the Netherlands Brain Bank. The Netherlands Brain Bank stores brain tissue from more than 5,000 deceased brain donors with a wide range of different brain diseases. What makes the Netherlands Brain Bank so unique is that, in addition to the stored tissue with very precise neuropathological diagnoses, they also keep the documented medical history and detailed disease course with the symptoms of each donor.

Resilient group

The team found a subgroup of people who had Alzheimer's disease processes in their brains, but did not show any clinical symptoms while alive. A so-called 'resilient' group. But how is it possible that they did not experience any symptoms while others did?

Luuk de Vries: 'what is happening in these people at a molecular and cellular level was not clear yet. We therefore searched for donors with brain tissue abnormalities who did not show cognitive decline in the Brain Bank. Of all the donors we found 12, so it is quite rare. We think that genetics and lifestyle play an important role in resilience, but the exact mechanism is still unknown.'

Keep challenging yourself

'Exercise or being cognitively active and having a lot of social contacts can help in delaying the onset of Alzheimer's disease. It has recently also been found that those who receive a lot of cognitive stimuli, like through a complex job, can build up more Alzheimer's pathology before developing symptoms. If we can find the molecular basis for resilience, then we have new starting points for the development of medication, which could activate processes related to resilience in Alzheimer's patients.'

Alzheimer's versus resilient group

'When we looked at gene expression, we saw that a number of processes were altered in the resilient group. First of all, the astrocytes appeared to produce more of the antioxidant metallothionein. Astrocytes are like garbage collectors and provide a protective role for the brain. Astrocytes often also ask for help from microglia, but because they can be quite aggressive, they sometimes worsen inflammation. In the resilient group a microglia pathway that's often linked to Alzheimer's disease appeared to be less active. In addition, we saw that the so-called "unfolded protein response," a reaction in brain cells that automatically removes a misfolded toxic protein, was affected in Alzheimer's patients, but was relatively normal in resilient individuals. Finally, we found indicators that there may also be more mitochondria in the brain cells resilient individuals, which ensures better energy production.'

Source: ScienceDaily

The vicious cycle of protein clumping in Alzheimer's disease and normal aging

 It has long been known that a hallmark of Alzheimer's disease, and most other neurodegenerative diseases, is the clumping together of insoluble protein aggregates in the brain. During normal disease-free aging, there is also an accumulation of insoluble proteins.

To date, approaches to treatments for Alzheimer's disease have not addressed the contribution of protein insolubility as a general phenomenon, instead focusing on one or two insoluble proteins. Buck researchers have recently completed a systematic study in worms that paints an intricate picture of the connections between insoluble proteins in neurodegenerative diseases and aging. Furthermore, the work demonstrated an intervention that could reverse the toxic effects of the aggregates by boosting mitochondrial health."Based on our discoveries, targeting insoluble proteins could provide a strategy for the prevention and treatment of a variety of age-related diseases," said Edward Anderton, PhD, a postdoctoral fellow in Gordon Lithgow's lab and co-first author of a study that appears in the May 16 issue of the journal GeroScience.

"Our study shows how maintaining healthy mitochondria can combat protein clumping linked to both aging and Alzheimer's," said Manish Chamoli, PhD, a research scientist in Gordon Lithgow's and Julie Andersen's lab, and co-first author of the study. "By boosting mitochondrial health, we can potentially slow down or reverse these harmful effects, offering new ways to treat both aging and age-related diseases."

Results support the geroscience hypothesis

The strong link between insoluble proteins promoting normal aging and diseases also builds a case for the bigger picture of how aging and age-related diseases occur. "We would argue that this work really supports the geroscience hypothesis that there is a common pathway to Alzheimer's disease and aging itself," said Buck Professor Gordon Lithgow. PhD, Vice President of Academic Affairs and the senior author of the study. "Aging is driving the disease, but the factors that put you on the track toward the disease actually occur very early."

The fact that the team found a core insoluble proteome enriched with numerous proteins that had not been considered before creates new targets for exploration, said Lithgow. "In some ways it raises the flag about whether we should be thinking about what Alzheimer's looks like in very young people," he said.

Source: ScienceDaily

Global life expectancy to increase by nearly 5 years by 2050 despite geopolitical, metabolic, and environmental threats

 The latest findings from the Global Burden of Disease Study (GBD) 2021, published today in The Lancet, forecast that global life expectancy will increase by 4.9 years in males and 4.2 years in females between 2022 and 2050.

Increases are expected to be largest in countries where life expectancy is lower, contributing to a convergence of increased life expectancy across geographies. The trend is largely driven by public health measures that have prevented and improved survival rates from cardiovascular diseases, COVID-19, and a range of communicable, maternal, neonatal, and nutritional diseases (CMNNs).This study indicates that the ongoing shift in disease burden to non-communicable diseases (NCDs) -- like cardiovascular diseases, cancer, chronic obstructive pulmonary disease, and diabetes -- and exposure to NCD-associated risk factors -- such as obesity, high blood pressure, non-optimal diet, and smoking -- will have the greatest impact on disease burden of the next generation.

As the disease burden continues to shift from CMNNs to NCDs and from years of life lost (YLLs) to years lived with disability (YLDs), more people are expected to live longer, but with more years spent in poor health. Global life expectancy is forecasted to increase from 73.6 years of age in 2022 to 78.1 years of age in 2050 (a 4.5-year increase). Global healthy life expectancy (HALE) -- the average number of years a person can expect to live in good health -- will increase from 64.8 years in 2022 to 67.4 years in 2050 (a 2.6-year increase).

To come to these conclusions, the study forecasts cause-specific mortality; YLLs; YLDs; disability-adjusted life years (DALYs, or lost years of healthy life due to poor health and early death); life expectancy; and HALE from 2022 through 2050 for 204 countries and territories.

"In addition to an increase in life expectancy overall, we have found that the disparity in life expectancy across geographies will lessen," said Dr. Chris Murray, Chair of Health Metrics Sciences at the University of Washington and Director of the Institute for Health Metrics and Evaluation (IHME). "This is an indicator that while health inequalities between the highest- and lowest-income regions will remain, the gaps are shrinking, with the biggest increases anticipated in sub-Saharan Africa."

Source: ScienceDaily

Two decades of studies suggest health benefits associated with plant-based diets

 Vegetarian and vegan diets are generally associated with better status on various medical factors linked to cardiovascular health and cancer risk, as well as lower risk of cardiovascular diseases, cancer, and death, according to a new review of 49 previously published papers. Angelo Capodici and colleagues present these findings in the open-access journal PLOS ONE on May 15, 2024.

Prior studies have linked certain diets with increased risk of cardiovascular disease and cancer. A diet that is poor in plant products and rich in meat, refined grains, sugar, and salt is associated with higher risk of death. Reducing consumption of animal-based products in favor of plant-based products has been suggested to lower the risk of cardiovascular disease and cancer. However, the overall benefits of such diets remain unclear.

To deepen understanding of the potential benefits of plant-based diets, Capodici and colleagues reviewed 48 papers published between January 2000 and June 2023 that themselves compiled evidence from multiple prior studies. Following an "umbrella" review approach, they extracted and analyzed data from the 48 papers on links between plant-based diets, cardiovascular health, and cancer risk.

Their analysis showed that, overall, vegetarian and vegan diets have a robust statistical association with better health status on a number of risk factors associated with cardiometabolic diseases, cancer, and mortality, such as blood pressure, management of blood sugar, and body mass index. Such diets are associated with reduced risk of ischemic heart disease, gastrointestinal and prostate cancer, and death from cardiovascular disease.

However, among pregnant women specifically, those with vegetarian diets faced no difference in their risk of gestational diabetes and hypertension compared to those on non-plant-based diets.

Overall, these findings suggest that plant-based diets are associated with significant health benefits. However, the researchers note, the statistical strength of this association is significantly limited by the many differences between past studies in terms of the specific diet regimens followed, patient demographics, study duration, and other factors. Moreover, some plant-based diets may introduce vitamin and mineral deficiencies for some people. Thus, the researchers caution against large-scale recommendation of plant-based diets until more research is completed.

The authors add: "Our study evaluates the different impacts of animal-free diets for cardiovascular health and cancer risk showing how a vegetarian diet can be beneficial to human health and be one of the effective preventive strategies for the two most impactful chronic diseases on human health in the 21st century."

Source: Science Daily