Genetic Mutation Accelerates CTE Pathology

Phosphorylated tau pS422 immunoreactive profiles in the cortex of P301Smice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu.

Phosphorylated tau pS422 immunoreactive profiles (dark brown) in the cortex of P301S mice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu, Department of Pathology, Johns Hopkins University.

Over the course of a football game or a boxing match, athletes may experience a series of mild concussions. Some of these athletes develop a condition known as chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by the build-up of abnormal tau protein that eventually leads to dementia. But not every athlete develops CTE after repetitive mild traumatic brain injury, and scientists think genetic factors are involved.

In a recent study, researchers at the Johns Hopkins University School of Medicine found that the density of abnormal tau protein increased exponentially in mice that had a genetic mutation thought to cause neurodegenerative diseases. Their findings contrast with previous studies of mice without genetic mutation, where abnormal tau protein build-up did not occur. This evidence leads the scientists to infer that genetic factors play a role in the onset of CTE.

Continue reading “Genetic Mutation Accelerates CTE Pathology” »

Researchers cited MBF systems in 24 papers between 11/2/2015 and 11/13/2015

Stereo Investigator:journal images sm

Bains, M., & Roberts, J. L. (2015). Estrogen protects against dopamine neuron toxicity in primary mesencephalic cultures through an indirect P13K/Akt mediated astrocyte pathway. Neuroscience Letters. doi:http://dx.doi.org/10.1016/j.neulet.2015.10.054.

Chen, M.-h., Liu, Y.-h., Xu, H., Xu, D.-w., Wang, C.-n., Wang, Y., . . . Wang, Y.-h. (2015). Lentiviral Vector-Mediated p27kip1 Expression Facilitates Recovery After Spinal Cord Injury. Molecular Neurobiology, 1-14. doi: 10.1007/s12035-015-9498-2.

Correa, M., Pardo, M., Bayarri, P., López-Cruz, L., San Miguel, N., Valverde, O., . . . Salamone, J. (2015). Choosing voluntary exercise over sucrose consumption depends upon dopamine transmission: effects of haloperidol in wild type and adenosine A2AKO mice. Psychopharmacology, 1-12. doi: 10.1007/s00213-015-4127-3.

Fragale, J. E. C., Khariv, V., Gregor, D. M., Smith, I. M., Jiao, X., Elkabes, S., . . . Beck, K. D. (2016). Dysfunction in amygdala–prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability. Experimental Neurology, 275, Part 3, 59-68. doi:http://dx.doi.org/10.1016/j.expneurol.2015.11.002.

Goodus, M. T., Kerr, N. A., Talwar, R., Buziashvili, D., Fragale, J. E. C., Pang, K., & Levison, S. W. (2015). LIF Haplodeficiency Desynchronizes Glial Reactivity and Exacerbates Damage and Functional Deficits After a Concussive Brain Injury. Journal of Neurotrauma. doi: 10.1089/neu.2015.4234.

Huang, Q., Du, X., He, X., Yu, Q., Hu, K., Breitwieser, W., . . . Li, M. (2015). JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson’s disease. Experimental Neurology. doi: http://dx.doi.org/10.1016/j.expneurol.2015.10.010.

Jayasinghe, V. R., Flores-Barrera, E., West, A. R., & Tseng, K. Y. (2015). Frequency-Dependent Corticostriatal Disinhibition Resulting from Chronic Dopamine Depletion: Role of Local Striatal cGMP and GABA-AR Signaling. Cerebral Cortex. doi: 10.1093/cercor/bhv241.

Kohl, Z., Abdallah, N. B., Vogelgsang, J., Tischer, L., Deusser, J., Amato, D., . . . Winkler, J. (2015). Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson’s disease. Neurobiology of Disease. doi:http://dx.doi.org/10.1016/j.nbd.2015.10.021.

Continue reading “Researchers cited MBF systems in 24 papers between 11/2/2015 and 11/13/2015” »

Dying neurons in Alzheimer’s patients show signs of improvement after gene therapy

nucleus basalis of Meynert

Micrograph of cholinergic neurons in the nucleus basalis of Meynert. Image from Wikipedia.

 

Cholinergic neurons degenerate at devastating rates in Alzheimer’s disease, but Dr. Mark Tuszynski and his team at the University of California, San Diego may have found a way to slow the decline.

Their study, published in JAMA Neurology, reports that nerve growth factor gene therapy increased the size, axonal sprouting, and signaling of cholinergic neurons in 10 Alzheimer’s disease patients.

The patients were enrolled in a clinical trial between 2001 and 2012. Ex vivo and in vivo methods of gene therapy were used to deliver nerve growth factor – a protein that protects neurons and stimulates growth – to the patients. Eight received an implant of their own skin cells that were genetically modified to express nerve growth factor (ex vivo ) and two patients received injections that induced neurons already in the brain to express nerve growth factor (in vivo). In all 10 patients, gene therapy was delivered to the nucleus basalis of Meynert – part of the basal forebrain rich in cholinergic neurons that undergoes degeneration during Alzheimer’s disease. 

The patients’ survival time ranged from one to 10 years. After they had died, researchers analyzed the effects of nerve growth factor on cholinergic neurons.

The axons of cholinergic neurons, labeled with p75, grew toward the source of the nerve growth factor in all 10 patients. To determine if there was a change in cell size, researchers used the nucleator probe in Stereo Investigator to analyze cholinergic neurons of 3 patients who received gene therapy via the ex vivo method in one hemisphere – the other hemisphere was used as a control. Results from Stereo Investigator showed that cell bodies were larger in the treated hemisphere vs. the untreated hemisphere.

Finally, to find out if nerve growth factor induced signaling within cells, the researchers analyzed the amount of CREB and c-fos – markers for cell activation – in 2 patients who received nerve growth factor in vivo. An elevated amount of CREB and c-fos was found when compared to control regions. Neurons exhibiting tau pathology also expressed nerve growth factor, indicating that degenerating cells could respond to nerve growth factor gene therapy.

A phase 2 clinical study is currently under way to report cognitive outcomes in patients with Alzheimer’s disease.

“Collectively, these anatomical findings support the rationale for clinical trials to test the hypothesis that sustained growth factor delivery over time can reduce cell degeneration and stimulate cell function in chronic neurodegenerative disorders, thereby slowing functional decline,” Tuszynski, et al.

Tuszynski, M.H., Yang, J.H., Pay, M.M., Masliah, E., Barba, D., U, H.S., Conner, J.M., Kobalka, P., Roy, S., and Nagahara A.H. (2015). Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurology, published online August 24, 2015. DOI: 10.1001/jamaneurol.2015.1807.

Researchers Explore Spatial Memory with Stereo Investigator

The researchers quantified c-Fos positive cells in the CA1 region of the hippocampus. Image provided by Dr. Matthew Holahan.

The researchers quantified c-Fos positive cells in the CA1 region of the hippocampus. Image provided by Dr. Matthew Holahan.

Spacial memories help us navigate places like the office, the local coffee shop, or the supermarket. The hippocampus plays a key role in processing and recalling spacial memory, but as time passes, there is evidence that the anterior cingulate cortex (ACC) becomes more involved in recalling these memories. A recent paper published in PLOS ONE further investigates the ACC and found that taxing the hippocampus with spacial memory tasks accelerates the recruitment of the ACC for spacial memory recall.

Continue reading “Researchers Explore Spatial Memory with Stereo Investigator” »

How Transplanted Stem Cells Behave in Injured Spinal Cord Tissue

A representative confocal image of spinal cord tissue fluorescently immunolabeled for SC121 in conjunction with GFAP – markers that allowed the researchers to track stem cell differentiation and migration by stereological quantification. (Image provided by study author Dr. Aileen J. Anderson)

A representative confocal image of spinal cord tissue fluorescently immunolabeled for SC121 (red) in conjunction with GFAP (green) – markers that allowed researchers to quantify stem cell differentiation and migration. (Image provided by study author Dr. Aileen J. Anderson)

Research has shown that transplanting human neural stem cells into damaged spinal cords restores locomotor function in a mouse model of spinal cord injury1. Researchers who worked on that study have published another paper examining how these neural stem cells behave in injured tissue as they aid in healing. Learning how stem cells behave in injured tissue will hopefully help researchers develop better treatments for spinal cord injuries.

In the study, researchers used Stereo Investigator to stereologically quantify the survival, migration, proliferation, and differentiation of human neural stem cells transplanted into injured and uninjured mice. Stem cells were analyzed in mouse brain tissue specimens 1, 7, 14, 28, and 98 days after transplantation. The research found that there were fewer stem cells in the injured animals compared to the uninjured animals at all time points, stem cells in injured mice localized near the center of the injury, a delay of stem cell proliferation in injured tissue led to an overall deficit of actively dividing cells, proliferation in injured mice occurred closer to the injection sites (the locations where the stem cells were injected into the mice), and the injured microenvironment increased differentiation to more mature oligodendrocytes.

Continue reading “How Transplanted Stem Cells Behave in Injured Spinal Cord Tissue” »

Delayed loss of neurons occurs in mice with mild TBI and anxiety

Almeida-Suhett et al saw delayed loss of GABAergic interneurons in the BLA within the first week after mild CCI. (Representative photomicrographs of GAD-67 immunohistochemically stained GABAergic interneurons in the BLA of sham (left), 1-day CCI (middle), and 7-day CCI (right) animals. Total magnification is 630x; scale bar, 50 µm.)

Almeida-Suhett et al saw delayed loss of GABAergic interneurons in the BLA within the first week after mild CCI. (Representative photomicrographs of GAD-67 immunohistochemically stained GABAergic interneurons in the BLA of sham (left), 1-day CCI (middle), and 7-day CCI (right) animals. Total magnification is 630x; scale bar, 50 µm.)

Soldiers, athletes, and other individuals who suffer a traumatic brain injury often develop anxiety disorders, but scientists aren’t sure why. Some speculate that fear about future health or the stress of the trauma itself contributes to elevated anxiety, while others suspect changes happening inside the brain as a result of the injury are to blame.

Researchers at Maria Braga’s lab at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, recently found direct evidence that physical changes happen in the brain after TBI that coincide with increased anxiety levels.

She and her team studied a rat model of mild TBI, focusing on the basolateral amygdala (BLA) – a brain region often damaged by TBI, which has also been associated with increased fear and anxiety in instances of hyperactivity.

To find out what happens in the BLA that might be causing anxiety after a mild TBI, the researchers analyzed changes in synaptic activity in this region. Using Stereo Investigator with the optical fractionator probe to perform a stereological quantification of Nissl-stained and GAD-67 immunostained brain cells, they found that many of the inhibitory neurons – the cells that quiet activity – were lost seven days after injury. Whole cell recordings from principal neurons confirmed that the inhibitory cells’ synaptic transmissions were impaired during this period, resulting in increased excitability and “open field tests” showed elevated anxiety levels in post-injury rats at the exact same time point. Continue reading “Delayed loss of neurons occurs in mice with mild TBI and anxiety” »

Higher levels of pTau found in Alzheimer’s disease patients with psychosis

murray_ptau

An image of neurofibrillary tangles and neuropil threads

People with Alzheimer’s disease suffer from severe memory loss and often have problems focusing, reasoning, and communicating. About half of all Alzheimer’s patients also experience delusions and hallucinations, this is called Alzheimer’s disease with psychosis, and scientists at the University of Pittsburgh are learning more about this severe version of the disease.

In a recent study, researchers at Dr. Robert Sweet’s lab zeroed in on a protein called tau, which forms tangles in the brains of Alzheimer’s patients, and along with amyloid plaques is one of the major hallmarks of the disease. But despite being involved in these pathological conditions, tau and amyloid may instigate other processes as well – namely, synaptic toxicity, which the authors say is “the strongest correlate of cognitive decline in Alzheimer’s disease.”

Recent research suggests that amyloids (misfolded proteins) drive the deterioration of synapses, but phospho-tau (tau, which has undergone phosphorylation), enables the process. So in their study the Pittsburgh research team analyzed the presence of tau in the prefrontal cortex, a region of the brain involved in higher processes, of 45 Alzheimer’s disease patients with and without psychosis.

Continue reading “Higher levels of pTau found in Alzheimer’s disease patients with psychosis” »

New Neurons Erase Memories

Dentate gyrus

Neurogenesis occurs in the dentate gyrus, pictured here, from birth through adulthood.

A baby laughs at an elephant at the zoo. A toddler runs across a beach. Small children make memories all the time, but how many will they recall as the years pass? Maybe none at all. The phenomenon is called “infantile amnesia,” and scientists may have pinpointed a reason for why it occurs – neurogenesis.

Researchers at the Hospital for Sick Children in Toronto say that when new brain cells integrate into existing circuitry, they remodel the structure of networks already in place, wiping out the information previously stored there. This process is prevalent in infancy and early childhood because this is the time when new brain cells are being generated faster and more frequently than at any other time in a human being’s life. Humans and other mammals spawn new neurons throughout their lifespans, although the rate of neurogenesis decreases significantly with age.

In their paper, published in Science, the researchers explain how recent studies have focused on how new brain cells can lead to new memories, but the Toronto team speculated that neurogenesis could also wipe away memories. To test their hypothesis, they conducted a series of studies on populations of newborn and adult mice. Neuron development in mice occurs in much the same way as in humans, with rapid cell genesis in infancy that tapers off with age.

Continue reading “New Neurons Erase Memories” »

Scientists Use Stereo Investigator in Spinal Cord Injury Study

Stereo Investigator Graphic

After an initial spinal cord injury, a cascading series of secondary events continues to do damage to the nervous system. One particularly damaging event is the death of oligodendrocytes—neuroglial cells that help protect and support the central nervous system. Scientists are learning more about the mechanisms involved in this process in the hope that their research may lead to the development of new therapeutic treatments for stopping some of the secondary damage before it occurs.

Researchers at the Miami Project to Cure Paralysis previously found that astrocytes play a role in oligodendrocyte death after spinal cord injury, but they weren’t quite sure how. Their new study identifies a culprit – an enzyme called NADPH oxidase. According to their paper, published in PLOS One, astrocytes activate NADPH oxidase within oligodendrocytes after an injury, triggering a toxic effect in the tiny neural cells.

In their study, the researchers set out to see what would happen if they could prevent post-trauma NADPH oxidase activation. Their results proved promising, with both in vitro and in vivo experiments resulting in lower oligodendrocyte death.

Continue reading “Scientists Use Stereo Investigator in Spinal Cord Injury Study” »

Scientists Map Photoreceptor Cells of Deep-Sea Sharks

Topographic mapping of photoreceptor cells. a Scleral eyecup with the retina uppermost, where peripheral slits have been made to allow flattening. The retina is then carefully removed from the sclera, freed of the underlying choroidal tapetum lucidum and wholemounted onto a non-subbed slide. Scale bar = 1 cm. b Screen shot taken from Stereo Investigator showing the green inclusion line and the red exclusion line overlaid on the rod photoreceptor array, viewed here on the axial plane. Colors are visible online only. Scale bar = 10 μm. c Optic nerve head as seen under a light microscope. Note the fascicles or bundles of ganglion cell axons converging on the optic nerve head. Scale bar = 200 μm.

a. Topographic mapping of photoreceptor cells. a Scleral eyecup with the retina uppermost, where peripheral slits have been made to allow flattening. The retina is then carefully removed from the sclera, freed of the underlying choroidal tapetum lucidum and wholemounted onto a non-subbed slide. Scale bar = 1 cm. b. Screen shot taken from Stereo Investigator showing the green inclusion line and the red exclusion line overlaid on the rod photoreceptor array, viewed here on the axial plane. Colors are visible online only. Scale bar = 10 μm. c. Optic nerve head as seen under a light microscope. Note the fascicles or bundles of ganglion cell axons converging on the optic nerve head. Scale bar = 200 μm.

The deepest parts of the ocean are dark. For marine animals living one thousand feet below sea level and lower, the absence of light makes it challenging to find food, attract a mate, and identify predators.

Some animals make their own light through a process called bioluminescence. Others have adapted in ways that help them detect light in an environment beyond the reach of the sun’s rays.

In the first stereological study of the eyes of deep sea sharks, scientists in Queensland, Australia quantified photoreceptor cell populations and mapped their topography in the retina of five different species of deep sea sharks.

The sharks, including the Borneo catshark, the longsnout dogfish, the prickly dogfish, the beige catshark, and McMillan’s catshark, were caught in the nets of deep-sea fishermen off the coast of New Zealand. Each type of shark featured large, round pupils and a tapetum lucidum, a reflective structure at the back of the eye – two common adaptations deep-sea animals use to enhance sensitivity in environments where bioluminescence is the only available light source, according to the paper.

Continue reading “Scientists Map Photoreceptor Cells of Deep-Sea Sharks” »