Jefferson Investigates: Guts to Joints, Traffic Patterns of Brain Molecules, and Immature Contacts in Alzheimer’s

The normal role of a gene involved in familial Alzheimer’s, neuronal clean-up crews, and how the gut microbiome might affect osteoarthritis

Exploring the Gut-Joint Connection in Osteoarthritis

Recently, scientists have been uncovering the wonders that lie in the bacteria of our guts. Not only does the gut microbiome aid in our digestion, but it has far reaching effects on our bodies, from our brain to our immune system. In a recent paper, Jefferson researchers explore a possible new linkage: the gut and our joints.

Probiotic bacteria Lactobacillus, 3D illustration. L. acidophilus, L. helveticus and other. Normal flora of intestine. Lactic acid bacterium

Emanuele Chisari, MD and current PhD student at Rothman Institute, in collaboration with the University of Groningen and under the supervision of Jefferson University and Rothman Institution orthopaedic surgeon Javad Parvizi, MD, reviewed the existing scientific literature to find evidence of connections between the gut microbiome and osteoarthritis. Their work suggests that the imbalance of certain bacteria within our microbiome can cause a chain reaction that leads to increased inflammation and immune response within our joints, worsening the symptoms and severity of osteoarthritis.

In particular, their work suggests that high-sugar diets, high-fat diets, and obesity likely act as stressors to the integrity of the gut barrier and the health of the microbiome. These stressors can lead to bacterial byproducts escaping the gut barrier into the circulatory system, later causing damage in joints such as the knee and hips. This can also trigger the production of cells that encourage inflammation which can also pass through the gut barrier. Over time, these effects lead to changes in osteoarthritis patients that can increase pain and decrease joint function.

While this research sheds light on the mechanisms through which the gut microbiome can aggravate osteoarthritis, it also points to possible solutions that may prevent the adverse impacts. Preliminary studies reviewed showed that pre- and probiotics may prevent and reverse these bacterial imbalances, curtailing a slow degeneration of joint function in patients. The authors recommend further clinical studies to validate these findings before changing any treatment regimens of osteoarthritis patients. Further study of the gut microbiome and joint relationship may provide insight for other joint related conditions as well, such as periprosthetic joint infection in patients with prosthetic joint replacements.
By Makhari Dysart

How Does Material Get Transported to the Right Place in Brain Circuits?

A single brain cell or neuron can send signals to hundreds of others using its axon – a thin fiber that acts like a telephone cable carrying electrical messages and splitting into numerous branches as it goes. Different cellular material needs to be transported along the axon and its elaborate branches, to support the development of brain circuits. How this transport is regulated has been a longstanding question in neurobiology. Now researchers in the lab of Le Ma, PhD, professor of neuroscience, provide some answers in a new study in Cell Reports.

The researchers cultured neurons in a dish and studied transport at the junction between two branches. They tagged a particular cellular cargo called lysosomes, small sacs that travel along branches removing waste and recycling nutrients. The researchers could then track the lysosomes’ movement in a living neuron and observe any changes. They found that if the two branches were the same length, the lysosomes traveled equally to both. However, if one branch was longer than the other, more lysosomes travelled to the longer one, suggesting that branch length can influence transport. Other structural properties like thickness and angle between the branches had no effect.

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Live-imaging of lysosomes (black dots) moving along the branches of an axon. Courtesy of the Ma Lab

“This previously unknown regulation helps us understand how two branches may compete to form connections with other neurons, and how transport is affected when one branch is damaged,” says Stephen Tymanskyj, PhD, the first author of the study.

They also looked at the influence of the growth cone – this is the tip of the branch that acts like a sensor, looking for things in the environment to grow toward or avoid. The researchers categorized the branches as having a dynamic growth cone, or a static one. They found that lysosomes selectively traveled to the more dynamic or motile branch. The researchers then used an optogenetic tool, using light to activate pathways that either promoted or inhibited growth cone motility. They found that when they artificially made a static branch more dynamic by turning on light, the lysosomes swarmed to that branch; conversely, when a dynamic branch is made static by light, the lysosomes moved to the other branch.

“We have created a simple assay to visualize and manipulate branch transport,” says Dr. Ma. “This allows us to explore other influencing factors and gives insight into conditions that impact brain circuits like nerve injury and memory loss.”
By Karuna Meda

The Normal Action of a Gene, Mutated in Alzheimer’s, Suggests Immature Brain Connections Could Lead to Neurodegeneration Later

Digitally generated close up Neurons cells

Artistic representation of neuronal synapses.

There’s a gene called presenilin that, as the “pre-senility” name connotes, is involved in neurodegenerative disease. In fact, this gene is the leading worldwide cause of inherited Alzheimer’s disease, when mutated. However, researchers still don’t fully understand what that gene does when it’s not mutated and whether it contributes to normal function in the brain. A new study from the lab of neuroscientist Tim Mosca, PhD, finds an unexpected and previously unknown role for presenilin in brain development. Using fruit flies, the group discovered that neuronal connections, or synapses, in the brain need presenilin to mature. Achieving synaptic maturation involves a complex series of events that ensure newly-formed contacts solidify into high-speed functional connections that allow us to move, think, learn and love. Their research was published in Developmental Cell.

Dr. Mosca’s lab then expanded the work to show how presenilin works in Alzheimer’s disease animal models. In the hereditary form of Alzheimer’s, they show that damage to this gene causes changes to neuronal communication early in life, which may increase the risk of developing Alzheimer’s disease.

In other words, based on these findings, the researchers hypothesize that synapses with presenilin mutations may not mature properly early on, but may still be capable of function. However, because they are not fully mature, neuronal connections may not withstand the test of time like properly matured synapses. “Then, when old age comes along or any other stress to the system that may happen when you’ve been running for 40, 50, 60 years, the neurons are much more likely to degrade and degenerate, thus causing what we recognize as the symptoms of neurodegenerative diseases like Alzheimer’s,” suggests Dr. Mosca. These findings provide a new perspective into how Alzheimer’s disease may develop, which could help identify earlier hallmarks of the disease, and eventually treatment.
By Edyta Zielinska

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