Detrimental effect of obesity on lesions associated with Alzheimer’s disease

Researchers from Inserm and the Université Lille/Université Lille Nord de France have recently used a neurodegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. This research was conducted on mice and is published in the Diabetes review: it corroborates the theory that metabolic anomalies contribute massively to the development of dementia.

In France, more than 860,000 people suffer from Alzheimer’s disease and related disorders, making them the largest cause of age-related loss of intellectual function. Cognitive impairments observed in Alzheimer’s disease result from the accumulation of abnormal tau proteins in nerve cells undergoing degeneration (see the picture below). We know that obesity, a major risk factor in the development of insulin resistance and type 2 diabetes, increases the risk of dementia during the aging process. However, the effects of obesity on ‘Taupathies’ (i.e. tau protein-related disorders), including Alzheimer’s disease, were not clearly understood. In particular, researchers assumed that insulin resistance played a major role in terms of the effects of obesity.

The “Alzheimer & Tauopathies” team from mixed research unit 837 (Inserm/Université Lille 2/Université Lille Nord de France) directed by Dr. Luc Buée, in collaboration with mixed research unit 1011 “Nuclear receptors, cardiovascular diseases and diabetes”, have just demonstrated, in mice, that obese subjects develop aggravated disorders. To achieve this result, young transgenic mice, who develop tau-related neurodegeneration progressively with age, were put on a high-fat diet for five months, leading to progressive obesity.

“At the end of this diet, the obese mice had developed an aggravated disorder both from the point of view of memory and modifications to the Tau protein”, explains David Blum, in charge of research at Inserm.

This study uses a neurodenegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. Furthermore, it indicates that insulin resistance is not the aggravating factor, as was suggested in previous studies.

“Our research supports the theory that environmental factors contribute massively to the development of this neurodegenerative disorder” underlines the researcher. “Our work is now focussing on identifying the factors responsible for this aggravation” he adds.

Can Blood Pressure Drugs Reduce the Risk of Dementia?

People taking the blood pressure drugs called beta blockers may be less likely to have changes in the brain that can be signs of Alzheimer’s disease and other types of dementia, according to a study released today that will be presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego, March 16 to 23, 2013. The study involved 774 elderly Japanese-American men who took part in the Honolulu-Asia Aging Study. Autopsies were performed on the men after their death. Of the 774 men, 610 had high blood pressure or were being treated with medication for high blood pressure. Among those who had been treated (about 350), 15 percent received only a beta blocker medication, 18 percent received a beta blocker plus one or more other medications, and the rest of the participants received other blood pressure drugs.

The study found that all types of blood pressure treatments were clearly better than no treatment. However, men who had received beta blockers as their only blood pressure medication had fewer abnormalities in their brains compared to those who had not been treated for their hypertension, or who had received other blood pressure medications. The brains of participants who had received beta blockers plus other medications showed an intermediate reduction in numbers of brain abnormalities.

These included two distinct types of brain lesion: those indicating Alzheimer’s disease, and lesions called microinfarcts, usually attributed to tiny, multiple, unrecognized strokes. Study participants who had taken beta blockers alone or in combination with another blood pressure medication had significantly less shrinkage in their brains.

“With the number of people with Alzheimer’s disease expected to grow significantly as our population ages, it is increasingly important to identify factors that could delay or prevent the disease,” said study author Lon White, MD, of the Pacific Health Research and Education Institute in Honolulu. “These results are exciting, especially since beta blockers are a common treatment for high blood pressure.”

Earlier research has shown that high blood pressure in midlife is a strong risk factor for dementia.

Molecular ‘Two-Way Radio’ Directs Nerve Cell Branching And Connectivity

Working with fruit flies, Johns Hopkins scientists have decoded the activity of protein signals that let certain nerve cells know when and where to branch so that they reach and connect to their correct muscle targets. The proteins’ mammalian counterparts are known to have signaling roles in immunity, nervous system and heart development, and tumor progression, suggesting broad implications for human disease research. A report of the research was published online Nov. 21 in the journal Neuron.

To control muscle movements, fruit flies, like other animals, have a set of nerve cells called motor neurons that connect muscle fibers to the nerve cord, a structure similar to the spinal cord, which in turn connects to the brain. During embryonic development, the nerve cells send wire-like projections, or axons, from the nerve cord structure out to their targets. Initially, multiple axons travel together in a convoy, but as they move forward, some axons must exit the “highway” at specific points to reach particular targets.

In their experiments, the researchers learned that axons travelling together have proteins on their surfaces that act like two-way radios, allowing the axons to communicate with each other and coordinate their travel patterns, thus ensuring that every muscle fiber gets connected to a nerve cell. “When axons fail to branch, or when they branch too early and too often, fruits flies, and presumably other animals, can be left without crucial muscle-nerve connections,” says Alex Kolodkin, Ph.D., a Howard Hughes investigator and professor of neuroscience at the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.

At the center of the communications system, Kolodkin says, is a protein called Sema-1a, already known to reside on the surface of motor neuron axons. If a neighboring axon has a different protein, called PlexA, on its surface, it will be repulsed by Sema-1a and will turn away from the axon bundle. So Sema-1a acts as an instructional signal and PlexA as its receptor. In the fruit fly study, the scientists discovered that Sema-1a can also act as a receptor for PlexA. “We used to think that this pair of surface proteins acted as a one-way radio, with information flowing in a single direction,” says Kolodkin. “What we found is that instructional information flows both ways.”

The Johns Hopkins team identified the “two-way” system by knocking out and otherwise manipulating fruit fly genes and then watching what happened to motor neuron branching. In these experiments, the researchers uncovered still other proteins located within the motor axons that Sema-1a interacts with after receiving a PlexA signal. When the gene for a protein called Pebble was deleted, for example, motor axons bunched together and didn’t branch. When the gene for RhoGAPp190 was deleted, motor axons branched too soon and failed to recognize their target muscles.

Through a series of biochemical tests, Kolodkin’s team found that Pebble and RhoGAPp190 both act on a third protein, Rho1. When Rho1 is activated, it collapses the supporting structures within an axon, making it “limp” and unable to continue toward a target. Sema-1a can bind to Pebble or to RhoGAPp190, and subsequently, these proteins can bind to Rho1. Binding to Pebble activates Rho1, causing axons to branch away from each other. However, binding to RhoGAPp190 shuts down Rho1, causing axons to remain bunched together. Thus, says Kolodkin, balance in the amounts of available Pebble and RhoGAPp190 can determine axon behavior, although what determines this balance is still unknown.

“This signaling is complex and we still don’t understand how it’s all controlled, but we’re one step closer now,” says Kolodkin. He notes that “a relative” of the Sema-1a protein in humans has already been implicated in schizophrenia, although details of this protein’s role in disease remain unclear. “Our experiments affirm how important this protein is to study and understand,” adds Kolodkin.

Mechanism of hearing is similar to car battery

University of Iowa biologist Daniel Eberl and his colleagues have shown that one of the mechanisms involved in hearing is similar to the battery in your car.

And if that isn’t interesting enough, the UI scientists advanced their knowledge of human hearing by studying a similar auditory system in fruit flies—and by making use of the fruit fly “love song.”

To see how the mechanism of hearing resembles a battery, you need to know that the auditory system of the fruit fly contains a protein that functions as a sodium/potassium pump, often called the sodium pump for short, and is highly expressed in a specialized support cell called the scolopale cell.

The scolopale cell is important because it wraps around the sensory endings in the fly’s ear and makes a tight extra-cellular cavity or compartment around them called the scolopale space.

“You could think of these compartments as similar to the compartments of a battery that need to be charged up so they can drive electrons through circuits,” says Eberl, whose paper made the cover of the journal Proceedings of the National Academy of Sciences. “In the auditory system, the charge in the scolopale space drives ions, or electrically charged atoms, through membrane channels in the sensory endings that open briefly in response to activation by sounds.

“Our work shows that the sodium pump plays a particularly important role in this cell to help replenish or recharge this compartment with the right ions. The human ear also relies on a compartment called the scala media, which similarly drives ions into the sensory cells of the ear,” he says.

How was the research done? This is where the fruit fly love song comes into play.

Testing whether or not a fruit fly can hear the love song—a sound generated by a vibrating wing—enables Eberl to learn whether electrical recharging is occurring in the fly ear. The fruit fly love song played a role in the research by stimulating the fly to move whenever a sound was emitted and received.

“In these experiments we tested the fly’s hearing by inserting tiny electrodes in the fly’s antenna, then measuring the electrical responses when we play back computer-generated love songs,” he says.

Eberl notes there are many similarities between fruit fly and human mechanisms of hearing. That means his work on the fly model to identify additional new components required for generating the correct ion balance in the ear will help scientists to understand the human process in more detail.

GE Silent Scan turns down the volume on MRI scanners

GE Healthcare has introduced a new data acquisition technology designed to improve patient comfort by largely eliminating the horrible noise generated during an MRI scan. Conventional MRI scanners can generate noise levels in excess of 110 dBA (creating a din that sounds like a cross between a vehicle’s reverse warning horn and a Star Trek phaser) but GE says its new Silent Scan MRI technology can reduce this to just above background noise levels in the exam room.

The noise that MRI scanners produce is related to changes in the magnetic field that allow the slice by slice body scan to be carried out. In recent years, industry efforts to speed up the scanning process have also resulted in louder and louder scans. The designers have attempted to dampen these noises with mufflers and baffles, achieving only limited success.

Silent Scan is achieved through two new developments. First, acoustic noise is essentially eliminated by using a new 3D scanning and reconstruction technique called Silenz. When the Silenz protocol is used in combination with GE’s new high-fidelity MRI gradient and RF system electronics, the MRI scanning noise is largely eliminated at its source.

At the 2012 meeting of the Radiological Society of North America, an MRI system compatible with the Silent Scan technology was linked into a soundproof room. When the MRI system used conventional scanning methods, a staccato, stuttering racket with noise peaks up to 110 dBA was heard. However, when Silent Scan was switched on, the noise level dropped to 76 dBA, just above the background noise of the MRI electronics. This is accomplished without substantial trade-offs in scanning time or image quality, according to Richard Hausmann, president and CEO, GE Healthcare MR. The comparison is shown in this video.

Silent Scan technology has not yet obtained 510k Premarketing Notification clearance from the FDA, so it’s not yet available for sale. GE is presumably hoping for a decision that Silent Scan is “substantially equivalent” to existing MRI scanners, a result that would greatly simplify the new technology’s entry into the diagnostic market.

Pronunciation of ‘s’ sounds impacts perception of gender

A person’s style of speech — not just the pitch of his or her voice — may help determine whether the listener perceives the speaker to be male or female, according to a University of Colorado Boulder researcher who studied transgender people transitioning from female to male.

The way people pronounce their “s” sounds and the amount of resonance they use when speaking contributes to the perception of gender, according to Lal Zimman, whose findings are based on research he completed while earning his doctoral degree from CU-Boulder’s linguistics department.

Zimman presented his research on Saturday, January 5th at the 2013 annual meeting of the Linguistic Society of America in Boston.

“In the past, gender differences in the voice have been understood, primarily, as a biological difference,” Zimman said. “I really wanted to look at the potential for other factors, other than how testosterone lowers the voice, to affect how a person’s voice is perceived.”

As part of the process of transitioning from female to male, participants in Zimman’s study were treated with the hormone testosterone, which causes a number of physical changes including the lowering of a person’s voice. Zimman was interested in whether the style of a person’s speech had any impact on how low a voice needed to drop before it was perceived as male.

What he found was that a voice could have a higher pitch and still be perceived as male if the speaker pronounced “s” sounds in a lower frequency, which is achieved by moving the tongue farther away from the teeth.

“A high-frequency ‘s’ has long been stereotypically associated with women’s speech, as well as gay men’s speech, yet there is no biological correlate to this association,” said CU-Boulder linguistics and anthropology Associate Professor Kira Hall, who served as Zimman’s doctoral adviser. “The project illustrates the socio-biological complexity of pitch: the designation of a voice as more masculine or more feminine is importantly influenced by other ideologically charged speech traits that are socially, not biologically, driven.”

Vocal resonance also affected the perception of gender in Zimman’s study. A deeper resonance — which can be thought of as a voice that seems to be emanating from the chest instead of from the head — is the result of both biology and practice. Resonance is lower for people whose larynx is deeper in their throats, but people learn to manipulate the position of their larynx when they’re young, with male children pulling their larynxes down a little bit and female children pushing them up, Zimman said.

For his study, Zimman recorded the voices of 15 transgender men, all of whom live in the San Francisco Bay area. To determine the frequency of the “s” sounds each participant made, Zimman used software developed by fellow linguists. Then, to see how the “s” sounds affected perception, Zimman digitally manipulated the recording of each participant’s voice, sliding the pitch from higher to lower, and asked a group of 10 listeners to identify the gender of the speaker. Using the recordings, Zimman was able to pinpoint how low each individual’s voice had to drop before the majority of the group perceived the speaker to be male.

Botox may help stroke patients

Injecting botox into the arm muscles of stroke survivors, with severe spasticity, changes electrical activity in the brain and may assist with longer-term recovery, according to new research.

Researchers at NeuRA (Neuroscience Research Australia) monitored nerve activity in the arms and brains of stroke survivors before and after botulinum toxin (botox) injections in rigid and stiff muscles in the arm.

They found that botox indeed improved arm muscles, but also altered brain activity in the cortex – the brain region responsible for movement, memory, learning and thinking.

“Botulinum toxin is used to treat a range of muscular and neurological conditions and our data shows that this treatment results in electrical and functional changes within the brain itself”, says Dr William Huynh, lead author of the study and a research neurologist at NeuRA.

“This effect of botox on the brain may arise because the toxin travels to the central nervous system directly, or because muscles treated with botox are sending different signals back to the brain”.

“Either way, we found that botox treatment in affected muscles not only improves muscle disorders in stroke patients, but also normalises electrical activity in the brain, particularly in the half of the brain not damaged by stroke”.

“Restoring normal activity in the unaffected side of the brain is particularly important because we suspect that abnormal information sent from affected muscles to the brain may be disrupting patients’ long-term recovery”, Dr Huynh concluded.

This paper is published in the journal Muscle and Nerve.

Specific protein essential for healthy eyes

Researchers at the Hebrew University of Jerusalem, in collaboration with researchers at the Salk Institute in California,  have found for the first time that a specific protein is essential not only for maintaining a healthy retina in the eye, but also may have implications for understanding and possibly treating other conditions in the immune, reproductive, vascular and nervous systems, as well as in various cancers.

Their work, reported online in the journal Neuron, highlights the role of Protein S in the maintenance of a healthy retina through its involvement in the process of pruning photoreceptors, the light-sensitive neurons in the eye. (This process is also referred to as phagocytosis.) These photoreceptors keep growing and elongating from their inner end. In order to maintain a constant length, they must be pruned from their outer end by specialized cells called retinal pigment epithelial cells.

Without such pruning — which also clears away many free radicals and toxic by-products generated during visual biochemical reactions — photoreceptors would succumb to toxicity and degenerate, leading if unchecked to blindness. A receptor molecule called Mer is a key in photoreceptor pruning, and is therefore vital for retinal health. Mutations in the mouse, rat and human Mer genes cause retinal degeneration, which finally leads to blindness.

The Hebrew University study published in Neuron focuses on the molecules activating Mer in this pruning mechanism. Although two such molecules – Gas6 and Protein S — were identified previously, it was yet to be proven that they also play a role in a living organism. To show this, Dr. Tal Burstyn-Cohen of the Hebrew University Institute of Dental Sciences and colleagues at the Salk Institute in California found in their experiments on laboratory animals that both Gas6 and Protein S are needed to activate phagocytosis, or pruning, of retinal photoreceptors, and thus keep a healthy retina.

These findings could have practical implications, since Protein S also functions as a potent blood anticoagulant. People with Protein S deficiency are at risk for life threatening thrombosis (blood clots) and thromboembolism (a clot that breaks loose and is carried by the blood stream to plug another vessel).

These results further open new avenues of research into the role of Protein S in activating the receptors in other tissues where their function was shown to be important, such as in the immune, reproductive, vascular and nervous systems, as well as in various cancers where activation of receptors has been observed. For example, since Protein S is important for blood vessel formation, neutralizing Protein S in the blood vessels supplying blood to cancer growths could interfere with the cancerous blood supply.

(Image: Gemma Bou/Getty Images)