Researchers have figured out the speed that neural networks in the cerebral cortex can delete sensory information is a bit of information per active neuron per second. The activity patterns of the neural network models are deleted nearly as soon as they are passed on from sensory neurons.
The scientists used neural network models based on real neuronal properties for the first time for these calculations. Neuronal spike properties were figured into the models which also helped show that the cerebral cortex processes were extremely chaotic.
Neural networks and this type of research in general are all helping researchers better understand learning and memory processes. With better knowledge about learning and memory, researchers can work toward treatments for Alzheimer’s disease, dementia, learning disabilities, PTSD related memory loss and many other problems.
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Science is bringing some understanding of the heritability, prevalence, and inner workings of one of the most devastating diseases.(left) A PET scan’s bright areas reveal the concentration of amyloid beta, a protein that forms a plaque in Alzheimer’s patients. The scan compares the brains of a healthy patient (left) and a patient suffering from Alzheimer’s (right). Image: Alzheimer’s Disease Education and Referral Center, NIH
This has been a big week in Alzheimer’s news as scientists put together a clearer picture than ever before of how the disease affects the brain. Three recently published studies have detected the disease with new technologies, hinted at its prevalence, and described at last how it makes its lethal progress through the brain.
The existence of two forms of Alzheimer’s—early- and late-onset—has long baffled scientists. Of the estimated five million Americans who suffer from Alzheimer’s, only a few thousand are diagnosed with an early-onset form of the affliction, which affects people before the age of 65. This rare early-onset form is thought to be hereditary and scientists have associated multiple genetic mutations contributing to its occurrence. Late-onset Alzheimer’s, although more common, has been the bigger mystery. One variant of the APOE gene-—sometimes known as the Alzheimer’s gene—is linked to the late-onset disease. But the APOE gene, unlike dominant early-onset genes, does not determine whether a person will ultimately have dementia.
Now there’s evidence that late-onset Alzheimer’s has a genetic basis similar to that of early-onset Alzheimer’s. By sequencing select genes associated with the latter, along with frontotemporal dementia, researchers at Washington University in Saint Louis and other institutions found that patients with late-onset Alzheimer’s carry some of the same genetic mutations as those with the early-onset form. The evidence, published on Wednesday in PLoS ONE, bolsters the argument that the forms of Alzheimer’s that appear at different life stages should be classified as the same disease. As to why the disease appears earlier in some cases, the scientists speculated that those patients diagnosed relatively early in life carry more genetic risk factors for the disease.
This study’s use of rapid genetic sequencing, the authors noted, may provide a model for more precise identification of dementias. Within the study, the researchers identified patients who may have been misdiagnosed as having Alzheimer’s; the genes of these patients suggested that they had another type of dementia. Given the heritable component, patients with a family history could be screened to detect and diagnose Alzheimer’s early.
Other genetic research unveiled in the past week or so has shed light on the biological processes that underlie how Alzheimer’s affects the brain. Certain mutations may lead to an increased production of a protein called amyloid beta in the region of the brain that creates memory. This excess amyloid beta, naturally secreted by brain cells, then becomes a complex called an oligomer. These oligomers may interrupt the signals transmitted between neurons. As in other neurodegenerative diseases like Parkinson’s or Huntington’s, the spread of oligomers appears to be driving the disease process.
Oligomer-linked diseases are relatively common, in part because oligomers can also play an essential biological role in the brain. A recent investigation using fruit flies reveals that the presence of a specific oligomer is actually required for the flies to form long-term memories.
In an early stage of Alzheimer’s, the naturally secreted amyloid beta protein builds up as oligomers in the brain, which then go on to form larger aggregates called plaques. Later in the disease, another aberrant form of a protein called tau starts to build up, in the entorhinal cortex. Normally, tau helps provide structure crucial to neuron functioning. The buildup of tau, however, causes the protein to tangle and eventually kill brain cells. What was unknown until recently, however, was how the tau protein spreads through different brain regions.
Two studies—one to be published in Neuron and the other published in PLoS ONE on Wednesday—have answered this question using brain samples from mice genetically engineered to express tau as it occurs in the human brain. Using a staining technique to highlight tau’s distribution in the brain, they compared samples from mice of different ages to analyze how tau moved through brain cells over time. They found the protein spread from neuron to neighboring neuron, traveling along synapses.
Understanding how this protein moves may allow scientists to stop tau in its tracks. “This opens up a whole new world of biology,” says Columbia University’s Karen Duff, an author on the study published in PLoS ONE. Tau is implicated in 30 different forms of dementia. In addition, the movement of tau may be similar to the spread of oligomers associated with Parkinson’s and Huntington’s. Nonetheless, we are still a long way from a therapeutic solution and stopping tau, which comes at a relatively late stage of Alzheimer’s, might be a very limited therapy.
As the world’s population continues to age, Alzheimer’s becomes a threat to more of us with every passing day. Although we may not yet have new treatments from this work, the take-away on these findings is clear: If we really are going to win the war, or even a battle, against Alzheimer’s, we need basic research that can delve into the complex biology that contorts proteins and kills brain cells to find treatments for this disease.
Frontotemporal dementia is caused by a breakdown of nerve cells in the frontal and temporal region of the brain (fronto-temporal lobe), which leads to, among other symptoms, a change in personality and behavior. The cause of some forms of frontotemporal dementia is a genetically determined reduction of a hormone-like growth factor, progranulin. Scientists around Dr. Anja Capell and Prof. Christian Haass have now shown that various drugs that are already on the market to treat malaria, angina pectoris or heart rhythm disturbances can increase the production of progranulin. Accordingly, these drugs are good candidates for treatment of this specific form of frontotemporal dementia.
The work has been published in the online edition of the scientific journal Journal of Neuroscience on February 2nd, 2011.
Progranulin is needed in the human brain as a protective factor for sensitive nerve cells, too little progranulin therefore results in a progressive neuronal cell death. As for almost every other gene, there are also two copies of the progranulin gene in the cell. In patients with progranulin dependent frontotemporal dementia, one of the two copies is defective, leading to a 50% reduction in progranulin levels. To rescue the lack of progranulin, the Munich researchers tested various substances for their ability to stimulate the remaining progranulin production and identified a drug called bafilomycin (BafA1). They then examined the molecular mechanism underlying the impact of BafA1 on progranulin more closely. Growth factors such as progranulin are produced in cellular membrane inclusions, known as vesicles. BafA1 has an alkalizing effect on these vesicles: After administration of BafA1 the interior of the vesicles is less acidic — and this increases the production of progranulin.
Impact of Baf1A and chloroquine on progranulin levels. (Credit: C. Haass)
This observation encouraged the researchers to investigate further alkalizing substances for their ability to raise progranulin levels. Among the substances that passed the test were three drugs that are already on the market to treat various diseases: a medication for angina pectoris (bepridil), one for heart rhythm problems (amiodarone) and the widely used malaria drug chloroquine. Chloroquine increased the progranulin level not only in experiments with mouse cells to normal, but also in cells from patients with the defective progranulin gene.
In a clinical study in collaboration with the University of London, the team of Prof. Haass and Dr. Capell will now investigate whether chloroquine actually helps against progranulin dependent frontotemporal dementia. The human studies can be started very soon, as chloroquine has been used on countless patients, so that serious side effects are not to be expected. Even though the Munich scientists are optimistic, Prof. Haass warns against exaggerated hopes. “Experience shows that the step from cell and animal models to the patient is always connected with considerable difficulties. It will take several years until we know, whether chloroquine can be used as therapy for progranulin dependent frontotemporal dementia,” says Haass.
1. A. Capell, S. Liebscher, K. Fellerer, N. Brouwers, M. Willem, S. Lammich, I. Gijselinck, T. Bittner, A. M. Carlson, F. Sasse, B. Kunze, H. Steinmetz, R. Jansen, D. Dormann, K. Sleegers, M. Cruts, J. Herms, C. Van Broeckhoven, C. Haass. Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase. Journal of Neuroscience, 2011; 31 (5): 1885 DOI: 10.1523/JNEUROSCI.5757-10.2011