In this article, I will present a selection of publications that came out in March. There were many interesting developments, both in fundamental neuroscience and neurology, and in the practical aspects of dealing with brain-related diseases and disorders.

In March, the scientific community marked the birthday of Sir Bernard Katz, German-born biophysicist who received the 1970 Nobel Price in Physiology and Medicine for his investigations of the properties of synapses. Together with Paul Fatt, Sir Katz discovered that neural transmitters are released into the synapses in defined “quantal” portions. The underlying mechanism of exocytosis relies on the release of neurotransmitters from the vesicles of approximately equal size, thus giving this seemingly quantum property to the process of neural transmission. The works of Bernard Katz laid foundation to the modern understanding of the processes of neural transmission.

THE BEST

Last month, we saw quite a few interesting and encouraging publications on the development of treatments for Alzheimer’s disease. All of these new approaches are still in their infancy, but the important thing is that they demonstrate not only the slowing down of disease development but also the possibility of restoring, at least partially, normal brain functions.

New anti-tau immunotherapy for Alzheimer’s

The oligomers of tau proteins are considered as one of the major culprits in the development and progression of Alzheimer’s disease. Scientists from the University of Texas tested the effect of new anti-tau immunotherapy on experimental animals with Alzheimer’s. It turned out that a single dose of immunotherapy reversed the memory deficit in animals. It also reduced the level of beta amyloid oligomers, the building blocks of notorious amyloid plaques that are always seen in the brains of patients with the disease. Clearly there is a cross-talk between two molecular components, since immunotherapy targeted directly only one of them.

Existing drugs to treat Alzheimer’s?

Two existing drugs have also been found active in reversing the effects of Alzheimer’s disease. An existing drug to treat epilepsy, levetiracetam, was found to be able to restore memory and brain functions in patients with amnestic mild cognitive impairment, which is considered an early stage of Alzheimer’s disease. The drug was tested in the first human trial and was shown to improve memory performance in the patients.

Another drug, AZD05030, was developed to treat cancer but failed clinical trials. Surprisingly, it turned out to be effective for Alzheimer’s disease, restoring the memory and brain cell connections in the experimental animals. The compound will soon be tested in clinical trials on humans.

Ultrasound to activate microglial cells

But the most interesting news, in my opinion, came from Australia. Researchers at the University of Queensland have developed a non-invasive ultrasound method that activates microglial cells making them to digest and remove the amyloid plaques. The treatment temporarily opens the blood-brain barrier thus allowing activation of mechanisms that clear away the toxic protein agglomerates from the brain. In the mice with Alzheimer’s disease, the treatment restored the memory to the healthy levels. If this approach will work in humans at least to some degree, it will most certainly represent a breakthrough in the treatment of Alzheimer’s disease.

The differences in young and old brains according to fMRI

Alzheimer’s disease is often considered as one of the common aspects of aging. But in general, the age-related negative changes in brain functions are traditionally viewed as a reflection of changes in the underlying neuronal activity. This view is challenged by new data obtained by researchers from the University of Cambridge.

The scientists re-examined methodology that is used to measure the brain activity, the functional magnetic resonance imaging (fMRI). The problem with fMRI is that it measures neural activity indirectly through changes in regional blood flow. This means that the differences in age-related vascular reactivity should be taken into account when neuronal differences are measured. Researchers used the resting state fMRI measurements from 355 healthy volunteers over their lifetime to get the baseline measures of vascular functions. Once these new baseline data were taken into account, the differences in neuronal activity between young and old brain turned out to be not so big, thus suggesting that they were overestimated in previous studies. The changes in the aging brain are likely to be caused primarily by the vascular changes.

Opening the blood-brain barrier with radiowaves

One of the reasons we have so few therapeutics to target brain diseases is the lack of reliable brain-specific drug delivery systems. The next article provides a radically different approach to address this problem.

Localized and specific drug delivery to the problem site in the body was always viewed by pharmaceutical scientists as a highly desirable aim which is, unfortunately, very difficult to achieve. With 98% of modern drugs unable to cross the blood-brain barrier, the brain is a particularly difficult part of the body to target selectively. A new approach reported by Canadian scientists this month sounds almost futuristic.

They developed a method of delivering magnetic nanoparticles to the specific areas of the brain using the magnetic fields generated by MRI machine. Once there, the nanoparticles can be made to by vibrate and dissipate heat using a radio-frequency field. This creates a mechanical stress that opens a blood-brain barrier locally and for a limited period of time (around 2 hours), thus allowing the delivery of blood-circulating therapeutics into the brain. The method has only been proven on the animals so far, but it appears to be a highly promising strategy for treating multiple brain disorders.

Free will for all?

Fundamental mechanisms of brain functioning continue to attract the attention of neuroscientists. In particular, we are interested in the characteristics of human brain that are unique to us. Free will is among those things that we see as making us who we are.

Well, the newly published study casts certain doubts on this self-glorifying view. It appears that even the animals as simple as worms have free will. Once tempted by the smell of tasty food, they may chose to go and investigate, but may also ignore it altogether and move in another direction. The brain of the microscopic roundworm Caenorhabditis elegans has only 302 neurons and 7,000 synapses. This is a nice simple model for investigating the function of neural systems.

Researchers found that the particular response of the individual worm to the stimulus depends on the current state of a simple three-cell neuronal system in its brain. This system can be influenced by competing motivations, and the final behavioral response is formed on the basis of input provided from all neurons. In general, this is not so different from the responses observed in much more complex brains. And probably this finding should not be so surprising. After all, free will is not just a philosophical concept – it also has lots to do with the decision-making processes in the brain.

THE WORST

As usual, this month we have seen a number of publications that have changed our views on some important issues. We may consider them as negative developments, but gaining any knowledge is always a positive thing.

Potential uses for brain stem cells may be limited

Stem cell therapy is one of the buzz words in the scientific community these days. The possibilities promised by this therapeutic approach are exciting. The discovery of stem cells in the brain brings hope that they can be used to treat a broad range of brain conditions, from neurodegenerative diseases to injuries. However, the new findings of German scientists will probably be seen as a certain setback for such high hopes. The researchers found that the diversity of neurons formed from them is limited. Also, the number of brain stem cells decreases with age. Further research will need to be focused on finding the ways to extend the ability of these cells to renew themselves.

We know less than we thought about inflammation in the brain

It is not uncommon to see scientific research yielding unexpected results. One of these such occasions was reported recently by the scientists from the University of Manchester studying stroke. It is well known that stroke is associated with inflammatory response which, instead of aiding recovery, cause further damage. Researchers were studying stroke-associated inflammasomes, large protein complexes mediating the inflammation and contributing to the cell death. One of such complexes called NLRP3 is known to be associated with injuries. Currently, the inflammasome NLRP3 is a target for developing the drugs against neurodegenerative diseases such as Alzheimer’s that is accompanied by inflammation.

To the researchers’ surprise, it turned out that NLRP3 has nothing to do with the inflammation processes in brain. Instead, two other protein complexes, NLRC4 and AIM2, are involved in the stroke and brain injury. The finding provides new targets for developing the stroke treatments, but also demonstrates once more how little we know about the inflammatory and immune processes in the brain.

Common treatments don’t always produce the results we want

Three publications below shed some light on why certain well established and commonly used treatments do not exactly produce the results we want.

Only in my previous monthly review I was mentioning that our knowledge of the mechanisms of anti-depressant drugs is limited at best. A new article published this month once again confirms this statement. It is generally believed that depression is caused by the imbalance in serotonin signalling. In response to the neuronal firing, serotonin is released from the vesicles in the presynaptic terminals into the synapse. Serotonin is then taken back into the terminals in the process which is targeted by the serotonin re-uptake inhibitors. The action of these drugs increases the level of serotonin in the synapses and thus normalize its balance affected during the depression.

It turned out, however, that exocytosis is not the only process for the serotonin release. The neuromediator can also simply diffuse through the cell membrane. The excessive level of serotonin may affect the firing of serotonergic neurons by autoinhibition, thus leading to the initial slowing down of the antidepressants’ therapeutic action.

HIV remains the largest pandemic in human history. Despite the decades of research and impressive success of anti-retroviral therapy, the complete cure for the disease remains elusive. The largest obstacle on the way to such cure is the presence of reservoirs in the body where the virus can safely hide from the circulating drugs. The brain is one of these reservoirs.

New data published this month show that the virus may infiltrate in the brain as early as four months after the initial infection. Once in the brain, virus may establish a relatively isolated sub-population which is mostly shielded from the drugs by the blood-brain barrier. Unfortunately, very little is currently known about the HIV replication inside the brain. Medical professionals commonly advise the HIV patients not to start the therapy immediately to avoid the long-term side effects of the drugs. Delaying the therapy, however, clearly helps the virus to establish itself in “safe havens” like brain, as current research demonstrates.

Obesity is one of the major risk factors in the development of type II diabetes. But the remarkable thing about the drugs for type II diabetes, such as thiazolidinediones, is that they make people to gain even more fat! Common sense would tell anyone that something is clearly wrong with these drugs. Now we know exactly what this is.

The drugs act directly on the so-called agouti-related protein (AgRP) cells, the hunger-stimulating cells located in the hypothalamus. Activation of these cells in experimental animals makes them immediately hungry. No wonder people treated by anti-diabetics feel much stronger food cravings. And obviously, something should be done with this whole approach to treat diabetes.

References

Bakker, A., Albert, M., Krauss, G., Speck, C., & Gallagher, M. (2015). Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance NeuroImage: Clinical, 7, 688-698 DOI: 10.1016/j.nicl.2015.02.009

Calzolari, F., Michel, J., Baumgart, E., Theis, F., Götz, M., & Ninkovic, J. (2015). Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone Nature Neuroscience, 18 (4), 490-492 DOI: 10.1038/nn.3963

Castillo-Carranza, D., Guerrero-Munoz, M., Sengupta, U., Hernandez, C., Barrett, A., Dineley, K., & Kayed, R. (2015). Tau Immunotherapy Modulates Both Pathological Tau and Upstream Amyloid Pathology in an Alzheimer’s Disease Mouse Model Journal of Neuroscience, 35 (12), 4857-4868 DOI: 10.1523/JNEUROSCI.4989-14.2015

Denes, A., Coutts, G., Lénárt, N., Cruickshank, S., Pelegrin, P., Skinner, J., Rothwell, N., Allan, S., & Brough, D. (2015). AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3 Proceedings of the National Academy of Sciences, 112 (13), 4050-4055 DOI: 10.1073/pnas.1419090112

Garretson, J., Teubner, B., Grove, K., Vazdarjanova, A., Ryu, V., & Bartness, T. (2015). Peroxisome Proliferator-Activated Receptor   Controls Ingestive Behavior, Agouti-Related Protein, and Neuropeptide Y mRNA in the Arcuate Hypothalamus Journal of Neuroscience, 35 (11), 4571-4581 DOI: 10.1523/JNEUROSCI.2129-14.2015

Gordus, A., Pokala, N., Levy, S., Flavell, S., & Bargmann, C. (2015). Feedback from Network States Generates Variability in a Probabilistic Olfactory Circuit Cell DOI: 10.1016/j.cell.2015.02.018

Kaufman, A., Salazar, S., Haas, L., Yang, J., Kostylev, M., Jeng, A., Robinson, S., Gunther, E., van Dyck, C., Nygaard, H., & Strittmatter, S. (2015). Fyn inhibition rescues established memory and synapse loss in Alzheimer mice Annals of Neurology DOI: 10.1002/ana.24394

Leinenga, G., & Gotz, J. (2015). Scanning ultrasound removes amyloid-  and restores memory in an Alzheimer’s disease mouse model Science Translational Medicine, 7 (278), 278-278 DOI: 10.1126/scitranslmed.aaa2512

Mlinar, B., Montalbano, A., Baccini, G., Tatini, F., Palmini, R., & Corradetti, R. (2015). Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity The Journal of General Physiology, 145 (3), 225-251 DOI: 10.1085/jgp.201411330

Sturdevant, C., Joseph, S., Schnell, G., Price, R., Swanstrom, R., & Spudich, S. (2015). Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection PLOS Pathogens, 11 (3) DOI: 10.1371/journal.ppat.1004720

Tabatabaei, S., Girouard, H., Carret, A., & Martel, S. (2015). Remote control of the permeability of the blood–brain barrier by magnetic heating of nanoparticles: A proof of concept for brain drug delivery Journal of Controlled Release, 206, 49-57 DOI: 10.1016/j.jconrel.2015.02.027

Tsvetanov, K., Henson, R., Tyler, L., Davis, S., Shafto, M., Taylor, J., Williams, N., Cam-CAN, ., & Rowe, J. (2015). The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults Human Brain Mapping DOI: 10.1002/hbm.22768

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