Author Archives: jpnd

A large, long-term study suggests that middle-aged people who have vascular health risk factors, including diabetes, high blood pressure and smoking, have a greater chance of suffering from dementia later in life. The study was published in JAMA Neurology.

The study analyzed the data of 15,744 people. From 1987-1989, the participants, who were black or white and 45-64 years of age, underwent a battery of medical tests during their initial examinations. Over the next 25 years they were examined four more times. Cognitive tests of memory and thinking were administered during all but the first and third exams.

Researchers found that 1,516 participants were diagnosed with dementia during an average of 23 follow-up years. Initially, when they analyzed the influence of factors recorded during the first exams, the researchers found that the chances of dementia increased most strongly with age followed by the presence of APOE4, a gene associated with Alzheimer’s disease. Whites with one copy of the APOE4 gene had a greater chance of dementia than blacks. Other factors included race and education: blacks had higher chance of dementia than whites; those who did not graduate from high school were also at higher risk.

In agreement with previous studies, an analysis of vascular risk factors showed that participants who had diabetes or high blood pressure, also called hypertension, had a higher chance of developing dementia. In fact, diabetes was almost as strong a predictor of dementia as the presence of the APOE4 gene.

Unlike other studies, the researchers discovered a link between dementia and prehypertension, a condition in which blood pressure levels are higher than normal but lower than hypertension. Also, race did not influence the association between dementia and the vascular risk factors they identified. Diabetes, hypertension and prehypertension increased the chances of dementia for white and black participants. Finally, smoking cigarettes exclusively increased the chances of dementia for whites but not blacks.

Paper: “Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort”

Reprinted from materials provided by the NIH/NINDS.

People who get less rapid eye movement (REM) sleep may have a greater risk of developing dementia, according to a new study published in the August 23, 2017, online issue of Neurology. REM sleep is the sleep stage when dreaming occurs.

There are five stages of sleep, ranging from light sleep to deep sleep to REM sleep. During this dream stage, the eyes move rapidly and there is increased brain activity as well as higher body temperature, quicker pulse and faster breathing. The first REM stage occurs about an hour to an hour-and-a-half into sleep and then recurs multiple times throughout the night as the cycles repeat.

For the study, researchers looked at 321 people with an average age of 67 over the course of 12 years on average. Researchers collected the participants’ sleep data. Over the course of the study, 32 people were diagnosed with some form of dementia, 24 of whom were diagnosed with Alzheimer’s disease.

Those who developed dementia spent less time in REM sleep: an average of 17 percent, compared to 20 percent for those who did not develop dementia. After adjusting for age and sex, researchers found links between both a lower percentage of REM sleep and a longer time to get to the REM sleep stage and a greater risk of dementia. In fact, for every percent reduction in REM sleep there was a 9 percent increase in the risk of dementia. The results were similar after researchers controlled for other factors that could affect dementia risk or sleep, such as heart disease factors, depression symptoms and medication use.

Other stages of sleep were not associated with an increased dementia risk.

Paper: “Sleep architecture and the risk of incident dementia in the community”

Reprinted from materials provided by the American Academy of Neurology.

Microglia, the brain’s immune cells responsible for eliminating pathogens and cellular waste, may live longer than researchers originally believed. A new study, published in an advance online publication of the journal Nature Neuroscience, shows that in mice these scavenger cells may live as long as the rodents themselves. The researchers followed individual microglia cells under the microscope in vivo. The unexpectedly long lifespan of microglia indicates further functions these cells may perform. Their longevity may permit them to form an immunological memory and contribute to the development of neurodegenerative diseases.

Until now it has been unclear whether microglia cells can create a memory for pathogens similar to the one developed by immune cells in the rest of the body.

Microglia have also long been suspected of playing a role in the development of age-related neurological diseases. It remains unclear how the cells contribute to the development of disease, however aging and senescence, which require the cells to live for a long time, may play a role.

In the healthy brain, the number of microglia remains more or less constant. The question until now has been whether microglia are short-lived, rapidly proliferating cells or whether they are long-lived cells that rarely divide. In the end, half of the cells studied showed a calculated lifespan of up to 28 months, which corresponds to a mouse’s lifetime, leading researchers to the conclusion that microglia are the latter.

Paper: “Microglia turnover with aging and in an Alzheimer´s model via long-term in vivo single-cell imaging

Reprinted from materials provided by Universitaet Tübingen.

Researchers studying the effects of immune cells surrounding blood vessels in the brain have discovered a new pathway involving these cells that may contribute to the cause of Alzheimer’s disease.

One of the hallmarks of Alzheimer’s disease is the accumulation of plaque deposits, or abnormal protein fragments, from a peptide called amyloid-beta. Amyloid-beta destroys neurons and damages brain blood vessels with the help of highly reactive molecules, called free radicals, which are derived from oxygen. In the study published in Circulation Research, the researchers sought to determine which cells in the brain were responsible for producing the free radicals, also known as reactive oxygen species (ROS).

The free radicals paralyze the vessels, preventing normal function. As a result, the brain cells are deprived of the oxygen and glucose they need to function correctly.

The investigators examined cells in the brain called perivascular macrophages (PVM), which surround blood vessels and pick up and remove damaging metabolic byproducts floating around the brain. The team focused on these cells because amyloid-beta tends to accumulate in the vascular space where PVM are located. They noticed that when cells are exposed to amyloid beta, the PMV begin to produce large quantities of free radicals.

To determine whether the PVM were involved in the ROS production, the researchers removed PVM by injecting into the brains of mice spherical lipid droplets called liposomes that contained the drug clodronate.

Researchers administered the liposomes in mice with Alzheimer’s disease; ROS paralyzed the blood vessels in the rodents. Remarkably, the team found that the blood vessels in these mice appeared to work normally once rid of PVM, despite the presence of amyloid-beta, demonstrating that without the PVM, amyloid beta did not exert its damaging effect on brain blood vessels.

Genetic studies have long suggested that the brain’s innate immune cells, like microglia and macrophages, contribute to Alzheimer’s disease, but how these cells damaged the brain was not known. The study demonstrates a novel way in which immune cells could contribute to Alzheimer’s disease and offer a new approach to treatment.

Paper: “Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

Reprinted from materials provided by Cornell University.

It has long been understood that a protein called TDP-43 clumps together in brain cells of people with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease, and is associated with neuron death. This same protein is thought to cause muscle degeneration in patients with sporadic inclusion body myositis (sIBM), leading many researchers to think that TDP-43 is one of the causative factors in ALS and sIBM. Now researchers have found that a specific chemical modification called acetylation promotes TDP-43 clumping in animals. Using a natural anti-clumping method in mouse models, the scientists reversed protein clumping in muscle cells and prevented the sIBM-related muscle weakness.

The discovery, published in Nature Communications, has important implications for understanding ALS and sIBM, and for the creation of potential treatments down the road.

TDP-43 normally works in the cell nucleus and appears to have many important functions in regulating how genes are expressed. In people with sIBM, ALS, and a few other degenerative diseases, TDP-43 moves out of the nucleus and into the main volume of the cell, or cytoplasm, and then clumps together. The loss of TDP-43 from the nucleus leads to the failure of normal gene expression regulation. Many scientists suspect that this is the major reason why affected cells die. In ALS, motor neuron death leads to the brain’s inability to control voluntary muscles throughout the body. In sIBM, muscle degeneration leads to muscle weakness and impaired strength.

For the study, researchers examined the effect of acetylated TDP-43 in living animals. In this case, they sought to mimic sIBM in mice, in which TDP-43 clumps in muscle cells.

The team used a special method to inject acetylated TDP-43 proteins directly into mouse muscle cells. In contrast to ordinary TDP-43 proteins, these acetylated proteins quickly aggregated outside the nucleus. The aggregate-burdened cells showed multiple features that are also seen in human sIBM.

The researchers observed cellular markers indicating that the muscle cells were actively trying to get rid of the TDP-43 aggregates. The team found that they could boost these cell defense mechanisms and swiftly remove most of the aggregates by adding heat shock factor 1 (HSF1), a naturally occurring protein that is known to work as a master switch for anti-aggregation processes in cells.

The team now hopes to identify compounds suitable for use in oral drugs that have the same anti-clumping effect.

Paper: “Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program.

Reprinted from materials provided by the University of North Carolina Health Care.

In a new study, researchers have found the first evidence that the activation of a biological pathway called necroptosis causes cells to die. This neuronal loss is closely linked with Alzheimer’s severity, cognitive decline and extreme loss of tissue and brain weight that are all hallmarks of the disease. The findings appear in Nature Neuroscience.

Necroptosis causes cells to burst from the inside out and die and is triggered by a triad of proteins. It has been shown to play a central role in multiple sclerosis and Lou Gehrig’ disease (amyotrophic lateral sclerosis, or ALS), and now for the first time, in Alzheimer’s disease as well. The brain of people with Alzheimer’s is smaller and weighs less due to shrinkage resulting from neuron death. Until now, the mechanism that triggered neuron death was not understood.

Three critical proteins are involved in the initiation of necroptosis, known as RIPK1, RIPK3 and MLKL. The study describes a key event in the process of necroptosis when RIPK1 and RIPK3 form a filamentous structure known as the necrosome. The formation of the necrosome appears to jump-start the process of necroptosis. It activates MLKL, which affects the cell’s mitochondria, eventually leading to cell death.

To explore necroptosis, the research team utilized multiple cohorts of human samples. First they measured RIPK1, RIPK3 and MLKL in the temporal gyrus, a region of the brain that is typically ravaged by cell loss during the advance of Alzheimer’s disease. Results showed that during necroptosis, these markers were increased in the brains of people with Alzheimer’s disease. Next, they identified the molecular cascade of necroptosis activation, with RIPK1 activating RIPK3 by binding with it. This protein complex then binds to and activates MLKL. Analysis of mRNA and protein revealed elevated levels of both RIPK1 and MLKL in the postmortem brain tissues of patients with Alzheimer’s when compared with normal postmortem brains.

Furthermore, they also demonstrated that necroptosis activation correlated with the protein tau. However necroptosis did not appear to be linked with beta-amyloid plaque, which is the other chief physiological characteristic of Alzheimer’s pathology.

The study also revisited the scores of patients whose postmortem brain tissue was evaluated for necroptosis. Results showed a significant association between RIPK1, MLKL and diminished scores on the Mini-Mental State Examination (MMSE), a widely used test measuring cognitive health.

Given the established relationship between necroptosis and Alzheimer’s pathology, including cell loss and attendant cognitive deficit, the study sought to inhibit the process to study the dynamic effects on cell death and memory loss. Since such experiments are not possible in people, the team used a mouse model  of the disease that demonstrated that lowering the activation of the necroptosis pathway reduces cell loss and improves performance in memory-related tasks, offering new hope for human therapeutics to halt or reverse the effects of Alzheimer’s.

The results reveal that the inhibition of necroptosis activation through the blockage of RIPK1 prevents cell loss in mice, offering hope for therapies targeting cell loss in the brain, an inevitable and devastating outcome of Alzheimer’s progression.

Paper: “New brain death pathway in Alzheimer’s disease: First of its kind study may lead to new era of Alzheimer’s drug discovery and therapeutic targets.

Reprinted from materials provided by Arizona State University.

A new discovery could help slow the progression of neurodegenerative diseases such as motor neuron disease (MND), dementia and neurological decline associated with ageing.

Researchers have identified that tuning up the activity pathway of the DNA’s natural repair toolkit — which normally helps to restore breakages in our genetic material — could help to prevent the death of nerve cells which trigger neurological diseases.

Scientists examined the C9orf72 gene which contains six DNA nucleotides. When this series of nucleotides is expanded and repeated multiple times, neurodegenerative diseases can occur. The expansions of the gene forms genetic material called ‘R-loops’ which make the DNA vulnerable to breakages. They found that accumulation of R-loops and increased DNA breakage in neurons lead to neurodegenerative diseases.

Our cells have their own repair toolkits specially designed to fix breaks in DNA, however, the products of the expansion over-activate a process called autophagy — a process that gets rid of misfolded or “unwanted” proteins. The new study, published in Nature Neuroscience, shows that the expansion-driven over-activation of this process can degrade some of the very precious DNA toolkits, meaning the cells will eventually die.

Researchers used genetic techniques to shut down the degradation process, which diminishes the cell’s capacity to repair genomic breaks. The discovery, based on work conducted in cellular and mouse models of the disease, could pave the way for new therapies for devastating diseases such as MND, which is one of the most common neurodegenerative disorders affecting younger people in the middle of their active life.

Paper: “C9orf72 expansion disrupts ATM-mediated chromosomal break repair.

Reprinted from materials provided by the University of Sheffield.