Brain cells of a laboratory mouse glowing with multicolor fluorescent proteins. Image courtesy of Harvard University, Livett-Weissman-Sanes-Lichtman
Early growth factor treatment may help prevent cell loss in Alzheimer’s disease
Four years ago, Mark Tuszynski, MD, PhD, professor of neurosciences at UC San Diego School of Medicine and director of the Center for Neural Repair and colleagues showed that a BDNF-based treatment measurably improved neural dysfunction in animal models of Alzheimer’s disease. The findings garnered international headlines.
Now there is new evidence that BDNF may be effective as a preventive measure for AD.
In a paper, published yesterday in The Journal of Neuroscience, Tuszynski and colleagues follow up with evidence that early life BDNF treatment prevents neuronal loss in mutant mice genetically predisposed to early-onset familial Alzheimer’s disease.
Specifically, mice engineered to express APP, a protein strongly linked to AD development, received injections of the BDNF gene at two months of age and were examined five months later. The researchers found that BDNF-treated mice exhibited better behavior and brain function than untreated APP mutant mice and suffered significantly less neuron loss in the entorhinal cortex, a region of the brain that helps mediate learning and memory.
In addition, they noted that BDNF did not affect amyloid plaque accumulation, another major indicator of AD, suggesting that direct amyloid reduction is not necessary to achieving significant neuroprotective benefits in mutant amyloid models of AD.
“These findings strengthen the rationale for planning human clinical trials of BDNF therapy in AD,” said Tuszynski. “This is an effort that we are actively engaged in.”
Tuszynski also noted that there is a possibility that BDNF therapy and anti-amyloid therapies for AD could be combined to yield better treatments than either treatment alone.
In this schematic, reduced activation in discrete medial prefrontal brain regions is depicted (in blue) in schizophrenia patients, occurring 0.2 seconds after sound changes (top panel), cascading forward to widespread brain regions associated with the automatic activation of attentional networks 0.1 second later (bottom panel).
Researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System have found that deficiencies in the neural processing of simple auditory tones can evolve into a cascade of dysfunctional information processing across wide swaths of the brain in patients with schizophrenia.
The findings are published in the current online edition of the journal Neuroimage.
Schizophrenia is a mental disorder characterized by disturbed thought processes and difficulty in discerning real from unreal perceptions. Common symptoms include auditory hallucinations and unfounded suspicious ideas. The disorder affects about 1 percent of the U.S. population, or roughly 3 million people.
“Impairments in the early stages of sensory information processing are associated with a constellation of abnormalities in schizophrenia patients,” said Gregory Light, PhD, associate professor of psychiatry at UC San Diego and senior author of the study.
These impairments, according to Light, may explain how schizophrenia patients develop clinical symptoms such as hearing voices that others cannot hear and difficulty with cognitive tasks involving attention, learning and recalling information. “If someone’s brain is unable to efficiently detect subtle changes in sounds despite normal hearing, they may not be able to automatically direct their attention and rapidly encode new information as it is being presented.”
Light and colleagues used electroencephalography – a technique that records patterns of electrical brain activity using electrodes positioned on the scalp – on 410 schizophrenia patients and 247 nonpsychiatric comparison subjects. The researchers employed novel computational imaging approaches to deconstruct the brain dynamics that underlie two leading neurobiological markers used in schizophrenia research: mismatch negativity (MMN) and P3a event-related potentials.
Neural Stem Cells Regenerate Axons in Severe Spinal Cord Injury
New relay circuits, formed across sites of complete spinal transaction, result in functional recovery in rats
In a study at the University of California, San Diego and VA San Diego Healthcare, researchers were able to regenerate “an astonishing degree” of axonal growth at the site of severe spinal cord injury in rats. Their research revealed that early stage neurons have the ability to survive and extend axons to form new, functional neuronal relays across an injury site in the adult central nervous system (CNS).
The study also proved that at least some types of adult CNS axons can overcome a normally inhibitory growth environment to grow over long distances. Importantly, stem cells across species exhibit these properties. The work will be published in the journal Cell on September 14.
(For a history of spinal cord repair science and the significance of this latest work, read Ohio State University neuroscientist Phillip Popovich’s review here.)
The UC San Diego-led team embedded neural stem cells in a matrix of fibrin (a protein key to blood-clotting that is already used in human neuron procedures), mixed with growth factors to form a gel. The gel was then applied to the injury site in rats with completely severed spinal cords.
“Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before,” said Mark Tuszynski, MD, PhD, professor in the UC San Diego Department of Neurosciences and director of the UCSD Center for Neural Repair, who headed the study. “The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement.”
In addition, adult cells above the injury site regenerated into the neural stem cells, establishing a new relay circuit that could be measured electrically. “By stimulating the spinal cord four segments above the injury and recording this electrical stimulation three segments below, we detected new relays across the transaction site,” said Tuszynski.
To confirm that the mechanism underlying recovery was due to formation of new relays, when rats recovered, their spinal cords were re-transected above the implant. The rats lost motor function – confirming formation of new relays across the injury.
The grafting procedure resulted in significant functional improvement: On a 21-point walking scale, without treatment, the rats score was only 1.5; following the stem cell therapy, it rose to 7 – a score reflecting the animals’ ability to move all joints of affected legs.
Results were then replicated using two human stem cell lines, one already in human trials for ALS. “We obtained the exact results using human cells as we had in the rat cells,” said Tuszynski.
The study made use of green fluorescent proteins (GFP), a technique that had never before been used to track neural stem cell growth. “By tagging the cells with GFP, we were able to observe the stem cells grow, become neurons and grow axons, showing us the full ability of these cells to grow and make connections with the host neurons,” said first author Paul Lu, PhD, assistant research scientist at UCSD’s Center for Neural Repair. “This is very exciting, because the technology didn’t exist before.”
Pictured: Artist’s rendering of neurons
Color-coded representations of human and mouse brains show similarities in cortical functional organization, with some variance according to species-specific needs. F/M indicates the frontal/motor cortex; S1, primary somatosensory cortex; A1, auditory cortex and V1, visual cortex.
Of Mice and Men, a Common Cortical Connection
MRI study finds genetic basis of brain development largely similar in mice and humans
A new study using magnetic resonance imaging data of 406 adult human twins affirms the long-standing idea that the genetic basis of human cortical regionalization – the organization of the outer brain into specific functional areas – is similar to and consistent with patterns found in other mammals, indicating a common conservation mechanism in evolution.
The findings by researchers at the University of California, San Diego School of Medicine and colleagues are published in the November 17 issue of the journal Neuron.
Past animal studies, primarily in rodents, have shown that development of distinct areas of the cortex – the outer layer of the brain – is influenced by genes exhibiting highly regionalized expression patterns. The new study is among the first to confirm these findings using data from human subjects. As in other mammals, the researchers found that that genetic influences in human brain development progress along a graduating scale anterior-to-posterior (front-to-back) in a bilateral, symmetric pattern.
There were, of course, differences based upon the particular needs and functions of each species.
Ferguson’s ability to remember the cities she’s lived in, jobs she’s worked and, yes, all the men she’s married, makes her very valuable to Jacopo Annese, a neuroanatomist at the University of California, San Diego. Annese is director of The Brain Observatory, a research center at UCSD where brains are sliced up, laid out on slides and then scanned into digital images, which researchers can use to visualize what a variety of brains look like. Scientists can use Annese’s images to see how diseases like Alzheimer’s physically change the brain.
Annese became well-known for his work with Henry Molaison, a famous amnesiac whose brain images will be studied by scientists across the world for insights into memory impairment.
"The Few, the Proud, the Brain Donors" (Voice of San Diego)