Tag: astrocytes

Categories : Neurodegenerative DiseasesTags :

How Astrocytes Know to Give the Brain an Energy Boost

On By ModernMedia
Image of an astrocyte, a subtype of glial cells. Glial cells are the most common cell in the brain. Credit: Pasca Lab, Stanford University

A key mechanism by which astrocytes detect when an energy boost is needed for the brain has been elucidated by University College of London researchers using mouse-based and in vitro studies.

The findings, published in Nature, could inform new therapies to maintain brain health and longevity, the researchers say, since other studies have found that brain energy metabolism can become impaired late in life and contribute to cognitive decline and the development of neurodegenerative disease.

Lead author Professor Alexander Gourine (UCL Neuroscience, Physiology & Pharmacology) said: “When our brain is more active, such as when we’re performing a mentally taxing task, our brain needs an immediate boost of energy, but the exact mechanisms that ensure on-demand local supply of metabolic energy to active brain regions are not fully understood.”

First and co-corresponding author Dr Shefeeq Theparambil, who began the study at UCL before moving to Lancaster University, said: “The normal activities of the brain require enormous amounts of energy, comparable to that of a human leg muscle running a marathon. This energy is primarily derived from blood glucose. Neurons in the brain consume more than 75% of this energy.”

Prior research has shown that numerous brain cells called astrocytes appear to play a role in providing the brain neurons with energy they need. Astrocytes, shaped like stars, are a type of glial cell, which are non-neuronal cells found in the central nervous system. When neighbouring neurons need an increase in energy supply, astrocytes jump into action by rapidly activating their own glucose stores and metabolism, leading to the increased production and release of lactate. Lactate supplements the pool of energy that is readily available for use by neurons in the brain.

Professor Gourine explained: “In our study, we have figured out how exactly astrocytes are able to monitor the energy use by their neighbouring nerve cells, and kick-start this process that delivers additional chemical energy to busy brain regions.”

In a series of experiments using mouse models and cell samples, the researchers identified a set of specific receptors in astrocytes that can detect and monitor neuronal activity, and trigger a signalling pathway involving an essential molecule called adenosine. The researchers found that the metabolic signalling pathway activated by adenosine in astrocytes is exactly the same as the pathway that recruits energy stores in the muscle and the liver, for example when we exercise.

Adenosine activates astrocyte glucose metabolism and supply of energy to neurons to ensure that synaptic function (neurotransmitters passing communication signals between cells) continues apace under conditions of high energy demand or reduced energy supply.

The researchers found that when they deactivated the key astrocyte receptors in mice, the animal’s brain activity was less effective, including significant impairments in global brain metabolism, memory and disruption of sleep, thus demonstrating that the signalling pathway they identified is vital for processes such as learning, memory and sleep.

Dr Theparambil said: “Identification of this mechanism may have broader implications as it could be a way of treating brain diseases where brain energetics are downregulated, such as neurodegeneration and dementia.”

Professor Gourine added: “We know that brain energy homeostasis is progressively impaired in ageing and this process is accelerated during the development of neurodegenerative diseases such as Alzheimer’s disease. Our study identifies an attractive readily druggable target and therapeutic opportunity for brain energy rescue for the purpose of protecting brain function, maintaining cognitive health, and promoting brain longevity.”

Categories : Cancer NeurologyTags :

Lung Cancer Metastases in the Brain Trick Astrocytes for Protection

On By ModernMedia
Small cell lung cancer cells (green and blue) that metastasised to the brain in a laboratory mouse recruit brain cells called astrocytes (red) for their protection. Credit: Fangfei Qu

Lung cancer cells that metastasise to the brain survive by convincing brain cells called astrocytes that they are baby neurons in need of protection, according to a study by researchers at Stanford Medicine published in Nature Cell Biology.

The cancer cells carry out their subterfuge by secreting a chemical signal prevalent in the developing human brain, the researchers found. This signal draws astrocytes to the tumour, encouraging them to secrete other factors that promote the cancer cells’ survival. Blocking that signal may be one way to slow or stop the growth of brain metastases of small cell lung cancer, which account for about 10% to 15% of all lung cancers, the researchers believe.

In the adult brain, astrocytes play a critical role in maintaining nerve function and connectivity. They are also important during brain development, when they facilitate connections between developing neurons.

The researchers studied laboratory mice, human tissue samples and human mini-brains, or organoids, grown in a lab dish to dissect the unique relationship between the cancer cells and their ‘big sister’ astrocytes, which hover nearby and shower them with protective factors.

“Small cell lung cancers are known for their ability to metastasise to the brain and thrive in an environment that is not normally conducive to tumour growth,” said professor of paediatrics and of genetics Julien Sage, PhD. “Our study suggests that these cancer cells reprogram the brain microenvironment by recruiting astrocytes for their protection.”

Professor Sage is the senior author of the study, while postdoctoral scholar Fangfei Qu, PhD, is the lead author.

Invasion of the brain

Small cell lung cancer excels at metastasising to the brain – about 15% to 20% of people already have clusters of cancer cells in their brains when their lung tumours are first diagnosed. As the cancer progresses, about 40% to 50% of patients will develop brain metastases. The problem is so prevalent, and the clinical outcome so dire, that clinicians recommend cranial radiation even before brain metastases have been found.

How and why small cell lung cancer has such an affinity for the brain has been something of a mystery. Brain metastases are rarely biopsied or removed because doing so has not been shown to affect a patient’s survival, and brain surgery is so invasive. Using laboratory mice is also of little help since small cell lung cancers in those animals rarely develop metastases in the brain, perhaps due to subtle biological differences between species.

Small cell lung cancers have another distinguishing feature – they are neuroendocrine cancers, meaning they arise from cells with similarities to both neurons and hormone-producing cells. Neuroendocrine cells link the nervous system with the endocrine system throughout the body, including in the lung.

Sage and his colleagues wondered whether neuronal-associated proteins on the surface of small cell lung cancer cells give them a leg up when the cells first begin to infiltrate the brain.

“We know the brain is full of neurons,” Sage said. “Maybe that’s why these cancer cells with some neuronal traits are happy in the brain and are accepted into that environment.”

Qu and Sage developed a way to inject mouse small cell lung cancer cells grown in the laboratory into the brains of mice to spark the development of brain tumours. They saw that astrocytes, a subtype of glial cell, flocked to the infant tumours and began to churn out proteins critical during brain development, including factors that stimulate nerve growth.

A plethora of astrocytes

A similar call happens in human brains, they noted: Brain tissue samples from people who had died of metastatic small cell lung cancer, shared by professor of pathology and paper co-author Christina Kong, MD, had many more protective astrocytes in the interior of the tumours than did metastases of melanoma, breast cancer and another type of lung cancer called adenocarcinoma.

Qu worked with assistant professor of paediatrics and co-author Anca Pasca, MD, to fuse aggregates of small cell lung cancer, lung adenocarcinoma or breast cancer cells with what are called cortical organoids – in vitro-grown clumps of brain cells including neurons and astrocytes that begin to mimic the organisation and connectivity of a human cortex. Within 10 days, many more protective astrocytes had infiltrated the small cell lung cancer pseudo-tumours than the adenocarcinoma or breast cancer.

“This showed us that the astrocytes actively move toward the small cell lung cancer cells, rather than simply being engulfed by the growing tumour,” Sage said. “What’s more exciting, though, is that these organoids, or mini-brains, realistically model the developing human brain. So, we’re no longer relying on a mouse model. It’s a perfect system to study brain metastases.”

Further research showed that the small cell lung cancer cells summon protective astrocytes by secreting a protein called Reelin that mediates the migration of neuronal and glial cells during brain development. Triggering Reelin expression in mouse breast cancer cells injected into the brain significantly increased the number of astrocytes in the resulting tumours in the mice, and the tumours were larger than in control animals injected with cells with low Reelin expression.

The apparent reliance of the cancer cells on chemical signals and responses specific to the developing brain may give clues for the development of future therapies, Sage believes.

“Some of these signals may not be as relevant or as highly expressed in the adult brain,” Sage said. “As a result, perhaps they could still be targeted to slow or prevent brain metastases without harming a normal brain. This might be an important window of opportunity for therapy.”

Source: Stanford Medicine