The Tech Gonzo Diary

Old proteins are cleaned up by "chaperone" molecules that dock with enzyme-filled compartments called lysosomes, where the unwanted molecules are recycled.

To extend the working life of the clean-up system, Cuervo's team made mice with an extra copy of the gene that codes for a receptor protein that lets the chaperone dock to the lysosome.

The team found that the livers of old mice with the extra gene worked just as well as the livers of young normal mice, and much better than those of old mice without the extra gene.

But how would this work in humans? We can't yet safely add genes to the cells of living people, but Cuervo explains that finding a drug that stops the existing receptor proteins breaking down could have the same effect.

"We are starting drug screening with the idea of looking for compounds that stabilise this particular receptor in the lysosomes," she says.

Diet hope

Better still would be to maintain the pathway through diet alone. "We know that the stability of this protein is related to changes in lipids," says Cuervo. A low-fat diet might therefore be able to prolong receptor life.

As this protein clearance pathway is used all over the body, Cuervo's team hope their finding will be relevant in other organs, such as the brain. In diseases like Alzheimer's and Parkinson's, an abnormal amount of proteins build up in the brain cells. Being able to improve the clearance of these proteins might allow us to delay the onset of symptoms.

How recycling could keep your organs young – health – 10 August 2008 – New Scientist.

Alzheimer’s disease patients show improvement in trial of new drug:

Seventy-eight participants with early stage Alzheimer's disease took either 50mg or 250mg doses of the drug PBT2, or a placebo, over the course of 12 weeks in a randomised, double-blind clinical trial, led by a researcher from Imperial College London working with colleagues in Australia and Sweden. Both doses of PBT2 capsules were observed to be safe and well tolerated during the course of the study.

Participants undertook a number of tests to assess their cognitive function, prior to beginning treatment and at the end of the 12-week period. In two of these tests of executive function, which involves the ability to organise information, sequence events and plan, those on a 250mg dose of PBT2 showed a significant improvement over the placebo group.

The researchers also measured how the levels of amyloid-beta in spinal fluid changed during the course of the trial. They found that levels of amyloid-beta 42 in the cerebrospinal fluid of those on the 250mg dose of PBT2 were reduced by approximately 13 percent compared to placebo at the end of the 12-week period.

Amyloid-beta needs the metals zinc and copper in order to accumulate in the brain and these two metals become abnormally distributed in the brains of people with Alzheimer's disease. PBT2 works by interrupting the interaction between the metal ions and amyloid-beta, and returns levels of zinc and copper in the brain to normal levels.

In the cognitive tests, those on a 250mg dose of PBT2 were able to complete the task in a test known as Trail Making Part B an average of 42 seconds faster than they had at the beginning of the trial. The placebo group was an average of 6 seconds slower.

In the Category Fluency Test, which looks at a person's ability to come up with as many relevant words as possible in relation to a specified category, those in the 250mg group were able to produce an average of 2.4 more words than at the beginning of the trial. This compared with a decrease of 0.3 words in the placebo group.

Although memory loss is the problem most often associated with Alzheimer's disease, the executive cognitive functions assessed by these two tests typically begin to deteriorate in the early stages of the disease, though are sometimes less obvious than memory symptoms.

..and if we take PBT2 while still healthy?!

Meanwhile, Aging impairs the ‘replay’ of memories during sleep:

During sleep, the hippocampus, a brain region important in learning and memory, repeatedly “replays” brain activity from recent awake experiences. This replay process is believed to be important for memory consolidation. In the new study, Carol Barnes, PhD, and colleagues at the University of Arizona found reduced replay activity during sleep in old compared to young rats, and rats with the least replay activity performed the worst in tests of spatial memory.

Barnes and colleagues recorded hippocampal activity in 11 young and 11 old rats as they navigated several mazes for food rewards. Later, when the animals were asleep, the researchers recorded their hippocampal activity again. In the young animals, the sequence of neural activity recorded while the animals navigated the mazes was repeated when they slept. However, in most of the old animals, the sequence of neural activity recorded during sleep did not reflect the sequence of brain activity recorded in the maze.

“These findings suggest that some of the memory impairment experienced during aging could involve a reduction in the automatic process of experience replay,” said Michael Hasselmo, DPhil, at Boston University, an expert unaffiliated with the study.

Animals with more faithful sleep replay also performed better on memory tests. The researchers tested the same 22 rats on a spatial learning and memory task. Consistent with previous research, the young rats recalled the solution to the spatial task faster and more accurately than the old rats. In the old group, the researchers found that the top performers in the spatial memory task were also the ones that showed the best sleep replay. Irrespective of the animal’s age, the researchers found that animals who more faithfully replayed the sequence of neural activity recorded in the maze while asleep also performed better on the spatial memory task.

“This is the first study to suggest that an animal’s ability to perform a spatial memory task may be related to the brain’s ability to perform memory consolidation during sleep,” said study author Barnes.

Identification of the specific memory deficit present in the aging brain may be a first step to preventing age-related memory loss. “This study’s findings could inspire the development and testing of pharmacological agents designed to enhance memory replay phenomena,” Hasselmo said.

‘course, when i think memory-consolidation during sleep, i’m thinking of synchronizing with cloned instances..

from Today@UCI: Press Releases:

Head and colleagues studied for a two-year period in aging canines the effect of a vaccine that is currently under clinical development for treating patients with Alzheimer’s disease. The vaccine contains the beta-amyloid 1-42 protein and stimulates the immune system to produce antibodies against this same protein that is in the brain plaques. Dogs are used for such studies because beta-amyloid plaques grow naturally in their brains and they exhibit cognitive declines similar to those seen in humans.

After the aged dogs with beta-amyloid-plaque growth were immunized (which is similar to starting a treatment in patients with Alzheimer’s disease), the researchers found, in comparison with non-treated aged dogs, little difference in the results of behavioral tests that measure cognitive loss. Later, brain autopsies showed that although plaques had been cleared from multiple brain regions – including the entorhinal cortex, a region of the brain involved with learning and memory and primarily affected by Alzheimer’s – damaged neurons remained.

Head said this discovery helps explain why there was little difference in the behavioral test results between immunized and nonimmunized dogs. In addition, she added, it implies that after clearing beta-amyloid plaques from the brain, the next step is to repair these neurons. This approach will be critical for treating and reversing the effects of the Alzheimer’s disease.

God, it’s taken them ages to be sure plaque was part of the problem.

Of course, once they figure out how to remove it, the next step is even harder.

Repairing neurons?! Short of recording all the connections before they degrade, I have no clue how they’re gonna fix this.

At least, that’s my what basic neuroscience tells me.

via

from Science News Online

Warming to a Cold War Herb

…

Growing at high altitudes from Scandinavia to Siberia, rhodiola has for centuries been a part of folk medicine among diverse native groups. Documented medicinal use reaches back at least to A.D. 77, when a physician to Roman legionnaires recommended it for headaches. In the 18th century, Linnaeus gave the herb its scientific name.

Soviet-government scientists Nikolai Lazarev and Israel Brekhman knew of this traditional use when, after World War II, they launched an extensive program to boost Soviet competitiveness in athletics and other demanding fields. The scientists tested nearly 200 herbal folk remedies and found 5, including rhodiola, particularly intriguing. They called the plants adaptogens for their ability to foster increased resistance to stress and to boost physical and mental performance. Unlike amphetamines, which the postwar Soviets also tested, these plants weren’t addictive, and users didn’t “crash” or suffer a rebound period of profound fatigue.

The adaptogens performed well on a pivotal test invented by the Soviets, an endurance swim for rats. When plopped into water, a rat will swim steadily for 10 to 15 minutes. Then it will float, paddling only as needed to keep from drowning. When the Soviet scientists gave rats rhodiola, the animals swam 35 percent to 59 percent longer. A modified version of the test is still used by academic researchers and drug companies to screen for potential new antidepressants.

By 1969, Soviet scientists had amassed enough evidence for the Ministry of Health to recommend rhodiola in its official list of medicines. Use of the herb took off.

“The Soviets were really invested in it,” says Georg Wikman of the Swedish Herbal Institute in Göteborg, who studies the herb. “There must be 300 to 400 reports published in quite good Russian-language journals.”

Much of the Soviet research on the herb remains untranslated or locked away because authorities considered adaptogen research a “top military secret,” Ramazanov maintained before his death last year. Nevertheless, he had translated some key findings by that time. In animals, the herb lowers production of the stress hormone cortisol. It acts as an antioxidant, helping to eliminate from the body the oxygen radicals that damage cells. And in muscles, it increases production of adenosine triphosphate, the molecule that serves as cellular gasoline.

Trials in people, while not up to Western standards, hinted that rhodiola could alleviate depression, erectile dysfunction and premature ejaculation, and chronic listlessness.

Other, higher quality trials suggested that the herb could boost athletic performance. A trial run by Victor Baranov at Moscow’s Institute for Space Medicine in the 1990s found that after taking rhodiola, inactive adults performed just as well as trained athletes in aerobic tests. During that experiment, researchers randomly assigned volunteers to take either the herb or a placebo, and participants, as well as their testers, were blind to which was which. Around the same time, another such randomized, double-blind study of 42 male biathletes reported improved target shooting in the group that took the herb. Also, the extract seemed to speed recovery of the athletes’ circulatory systems. Thirty minutes after the skiing part of the biathlon, the hearts of those who took the extract were beating at 105 percent of prerace rates, compared with 129 percent of precompetition rates among athletes who took a placebo.

In the late 1980s, researchers at the Russian Academy of Sciences in Moscow, home to much of the adaptogen work, discovered that three compounds found only in the rosea type of Rhodiola—there are at least 200 related species—were responsible for much of the plant’s activity. They dubbed these compounds rosavins, and in 1989 the Soviet government declared that all rhodiola extracts must contain at least 3 percent rosavins. Dietary supplement makers throughout the world still hew to this standard.

Even before the discovery of rosavins, Soviet adaptogen research culminated with ADAPT, a mixture of extracts from R. rosea, a species of ginseng, and a berry called Schizandra chinensis. Hoping for a synergistic effect, the Soviets gave ADAPT to Olympic athletes, according to Ramazanov’s self-published material.

The Soviets then decided to test ADAPT in their space program, a plan that enlisted Wikman and the Swedish Herbal Institute. Wikman and the Soviet scientists gave ADAPT to 60 sleep-deprived cosmonaut trainees. “Those tests went well,” says Wikman. The mixture “had a very clear effect on mental-work capacity, problem solving, and short-term memory when the subjects were really, really tired after staying up for days.” The mixture also helped normalize an elaborate measure of cardiac function in the sleep-deprived trainees. “So the decision was made to take it up, use it in space,” Wikman says.

Cosmonaut Valery Polyakov, a physician, took ADAPT daily while commander of the Mir space station during his 14-month mission in 1994 and 1995, says Wikman. Wikman adds that Polyakov credited ADAPT with helping him endure the record-length spaceflight.

…

Since the turn of the century, a growing number of reports investigating rhodiola have appeared in English-language journals. Several groups of researchers have found that, in the laboratory, rhodiola inhibits the spread of bacteria, prevents immune system damage caused by anticancer drugs, slows the division of cancer cells, and corrects enzyme irregularities in diabetic mice.

Meanwhile, Wikman and the Swedish Herbal Institute, which makes a rhodiola extract called SHR-5, have continued laboratory and human tests. In 2000, they reported that SHR-5 protects snail embryos from heat, copper, and oxidative stress. When given the herb extract, fewer of the embryos died after exposure to these stressors than did embryos not given the extract.

Also in 2000, Wikman and his colleagues in Russia published results from a randomized, double-blind trial of university students who took SHR-5 at the end of a semester. Students taking the herb for 20 days fared better on measures of fatigue and mental performance than did students who took a placebo. Another study published in 2000 found an antifatigue effect of the herb among 56 physicians working night shifts.

In 2003, the Swedish-Russian group published a study of 100 male military cadets who took a single dose of SHR-5. After working all night, 40 cadets received a low dose of the extract, 40 a high dose, and 20 a placebo. The cadets taking either dose of the extract scored higher on a battery of concentration and mental-performance tests than did cadets taking the placebo.

Most recently, in the September-October Nordic Journal of Psychiatry, Wikman and coworkers in Armenia report a randomized, double-blind trial in people with mild-to-moderate depression. For 6 weeks, two groups of 30 patients took either of two doses of SHR-5 while a third group took a placebo. People taking either dose of the extract reported fewer symptoms on standard depression questionnaires at the end of the study than did those who took the placebo.

“I’ve been using it as an antidepressant for years now,” says Columbia University’s Brown. “But it’s nice to have that validated in a clinical trial.”

via

from PhysOrg

Discovery supports theory of Alzheimer’s disease as form of diabetes

Insulin, it turns out, may be as important for the mind as it is for the body. Research in the last few years has raised the possibility that Alzheimer’s memory loss could be due to a novel third form of diabetes.

Now scientists at Northwestern University have discovered why brain insulin signaling — crucial for memory formation — would stop working in Alzheimer’s disease. They have shown that a toxic protein found in the brains of individuals with Alzheimer’s removes insulin receptors from nerve cells, rendering those neurons insulin resistant. (The protein, known to attack memory-forming synapses, is called an ADDL for “amyloid ß-derived diffusible ligand.”)

With other research showing that levels of brain insulin and its related receptors are lower in individuals with Alzheimer’s disease, the Northwestern study sheds light on the emerging idea of Alzheimer’s being a “type 3” diabetes.

The new findings, published online by the FASEB Journal, could help researchers determine which aspects of existing drugs now used to treat diabetic patients may protect neurons from ADDLs and improve insulin signaling in individuals with Alzheimer’s. (The FASEB Journal is a publication of the Federation of American Societies for Experimental Biology.)

In the brain, insulin and insulin receptors are vital to learning and memory. When insulin binds to a receptor at a synapse, it turns on a mechanism necessary for nerve cells to survive and memories to form. That Alzheimer’s disease may in part be caused by insulin resistance in the brain has scientists asking how that process gets initiated.

“We found the binding of ADDLs to synapses somehow prevents insulin receptors from accumulating at the synapses where they are needed,” said William L. Klein, professor of neurobiology and physiology in the Weinberg College of Arts and Sciences, who led the research team. “Instead, they are piling up where they are made, in the cell body, near the nucleus. Insulin cannot reach receptors there. This finding is the first molecular evidence as to why nerve cells should become insulin resistant in Alzheimer’s disease.”

ADDLS are small, soluble aggregated proteins. The clinical data strongly support a theory in which ADDLs accumulate at the beginning of Alzheimer’s disease and block memory function by a process predicted to be reversible.

In earlier research, Klein and colleagues found that ADDLs bind very specifically at synapses, initiating deterioration of synapse function and causing changes in synapse composition and shape. Now Klein and his team have shown that the molecules that make memories at synapses — insulin receptors — are being removed by ADDLs from the surface membrane of nerve cells.

“We think this is a major factor in the memory deficiencies caused by ADDLs in Alzheimer’s brains,” said Klein, a member of Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center. “We’re dealing with a fundamental new connection between two fields, diabetes and Alzheimer’s disease, and the implication is for therapeutics. We want to find ways to make those insulin receptors themselves resistant to the impact of ADDLs. And that might not be so difficult.”

Using mature cultures of hippocampal neurons, Klein and his team studied synapses that have been implicated in learning and memory mechanisms. The extremely differentiated neurons can be investigated at the molecular level. The researchers studied the synapses and their insulin receptors before and after ADDLs were introduced.

They discovered the toxic protein causes a rapid and significant loss of insulin receptors from the surface of neurons specifically on dendrites to which ADDLs are bound. ADDL binding clearly damages the trafficking of the insulin receptors, preventing them from getting to the synapses. The researchers measured the neuronal response to insulin and found that it was greatly inhibited by ADDLs.

“In addition to finding that neurons with ADDL binding showed a virtual absence of insulin receptors on their dendrites, we also found that dendrites with an abundance of insulin receptors showed no ADDL binding,” said co-author Fernanda G. De Felice, a visiting scientist from Federal University of Rio de Janeiro who is working in Klein’s lab. “These factors suggest that insulin resistance in the brains of those with Alzheimer’s is a response to ADDLs.”

“With proper research and development the drug arsenal for type 2 diabetes, in which individuals become insulin resistant, may be translated to Alzheimer’s treatment,” said Klein. “I think such drugs could supercede currently available Alzheimer’s drugs.”

– will the biggest win from the obesity epidemic be a cure for Alzheimer’s?