Discovery of New Drug Targets for Memory Impairment in Alzheimer’s Disease

We are now a step closer to having a drug that can cure dementia and memory loss. Research team in Korea has discovered that reactive astrocytes, which have been commonly observed in Alzheimer’s patients, aberrantly and abundantly produce the chief inhibitory neurotransmitter GABA and release it through the Best1 channel. The released GABA strongly inhibits neighboring neurons to cause impairment in synaptic transmission, plasticity and memory. This discovery will open a new chapter in the development of new drugs for treating such diseases.

Alzheimer’s disease, which is the most common cause of dementia, is fatal and currently, there is no cure. In Alzheimer’s disease, brain cells are damaged and destroyed, leading to devastating memory loss. It is reported that 1 in 8 Americans aged 65 or over have Alzheimer’s disease. In 2011, 7,600 elderly people with dementia lost their way back home and became homeless in Korea. However, to date, there has been no clear understanding of the mechanisms underlying dementia in Alzheimer’s disease. So far, neuronal death is the only proposed mechanism available in scientific literature.

The research team discovered that reactive astrocytes in the brains of Alzheimer’s disease model mice produce the inhibitory transmitter GABA by the enzyme Monoamine oxidase B(MAO-B) and release GABA through the Bestrophin-1 channel to suppress normal information flow during synaptic transmission. Based on this discovery, the team was able to reduce the production and release of GABA by inhibiting MAO-B or Bestrophin-1, and successfully ameliorate impairments in neuronal firing, synaptic transmission and memory in Alzheimer’s disease model mice.

In the behavioral test, the team used the fact that mice tend to prefer dark places. If a mouse experiences an electric shock in a dark place, it will remember this event and avoid dark places from then on. However, a mouse with modeled Alzheimer’s disease cannot remember if such shock is related to dark places and keeps going back to dark places. The team demonstrated that treating these mice with a MAO-B inhibitor fully recovered the mice’s memory. The selegiline is currently used in Parkinson’s disease as an adjunct therapy and considered as a one of best promising medicine for MAO-B inhibitor. But it has been previously shown to be less effective in Alzheimer’s disease.

The team proved that selegiline is effective for a short time, but when it is used in long term, it loses its efficacy in Alzheimer’s disease model mice. When treated for 1 week, selegiline brought the neuronal firing to a normal level. But when it was treated for 2 and 4 weeks, neuronal firing came back to the levels of untreated mice. From these results, the team proposed that there is a pressing need for a new drug that has long lasting effects.

Dr. C. Justin Lee said, “From this study, we reveal the novel mechanism of how Alzheimer’s patients might lose their memory. We also propose new therapeutic targets, which include GABA production and release mechanisms in reactive astrocytes for treatment of Alzheimer’s disease. Furthermore, we provide a stepping stone for the development of MAO-B inhibitors with long lasting efficacy.”

Discovery of new means to erase pain

A study published in the scientific journal Nature Neuroscience by Yves De Koninck and Robert Bonin, two researchers at Université Laval, reveals that it is possible to relieve pain hypersensitivity using a new method that involves rekindling pain so that it can subsequently be erased. This discovery could lead to novel means to alleviate chronic pain.

The researchers from the Faculty of Medicine at Université Laval and Institut universitaire en santé mentale de Québec (IUSMQ) were inspired by previous work on memory conducted some fifteen years ago. These studies had revealed that when a memory is reactivated during recall, its neurochemical encoding is temporarily unlocked. Simultaneous administration of a drug that blocks neurochemical reconsolidation of the memory results in its erasure.

The investigators wanted to see whether a similar mechanism was at play during neurochemical encoding of pain sensitization. To this end, they injected capsaicin in the foot of mice. Capsaicin, the pungent chemical in chili pepper, triggers a burning sensation. The procedure, which causes no physical damage, triggers pain hypersensitivity through a process of protein synthesis in the spinal cord. After capsaicin injections, the mechanical pressure at which mice would flinch was about a third of that in the normal situation.

Three hours later, the researchers administered a second dose of capsaicin and, at the same time, a drug that blocks protein synthesis. The hypersensitivity then vanished rapidly. Within less than 2 hours, the pressure tolerated by the mice was back to 70% of normal.

Yves De Koninck explains that “when the protein synthesis inhibitor is administered alone, the hypersensitivity remains. The second injection of capsaicin is necessary to render the sensitivity to pain unstable and be able to interfere with its neurochemical reconsolidation. The challenge now will be to find protein synthesis inhibitors that are nontoxic and cause minimal side effects in humans”.

Restoring Active Memory Program Poised to Launch

Teams will develop and test implantable therapeutic devices for memory restoration in patients with memory deficits caused by disease or trauma

DARPA has selected two universities to initially lead the agency’s Restoring Active Memory (RAM) program, which aims to develop and test wireless, implantable “neuroprosthetics” that can help servicemembers, veterans, and others overcome memory deficits incurred as a result of traumatic brain injury (TBI) or disease.

The University of California, Los Angeles (UCLA), and the University of Pennsylvania (Penn) will each head a multidisciplinary team to develop and test electronic interfaces that can sense memory deficits caused by injury and attempt to restore normal function. Under the terms of separate cooperative agreements with DARPA, UCLA will receive up to $15 million and Penn will receive up to $22.5 million over four years, with full funding contingent on the performer teams successfully meeting a series of technical milestones. DARPA also has a cooperative agreement worth up to $2.5 million in place with Lawrence Livermore National Laboratory to develop an implantable neural device for the UCLA-led effort.

“The start of the Restoring Active Memory program marks an exciting opportunity to reveal many new aspects of human memory and learn about the brain in ways that were never before possible,” said DARPA Program Manager Justin Sanchez. “Anyone who has witnessed the effects of memory loss in another person knows its toll and how few options are available to treat it. We’re going to apply the knowledge and understanding gained in RAM to develop new options for treatment through technology.”

TBI is a serious cause of disability in the United States. Diagnosed in more than 270,000 military servicemembers since 2000 and affecting an estimated 1.7 million U.S. civilians each year, TBI frequently results in an impaired ability to retrieve memories formed prior to injury and a reduced capacity to form or retain new memories following injury. Despite the scale of the problem, no effective therapies currently exist to mitigate the long-term consequences of TBI on memory. Through the RAM program, DARPA seeks to accelerate the development of technology needed to address this public health challenge and help servicemembers and others overcome memory deficits by developing new neuroprosthetics to bridge gaps in the injured brain.

“We owe it to our service members to accelerate research that can minimize the long-term impacts of their injuries,” Sanchez said. “Despite increasingly aggressive prevention efforts, traumatic brain injury remains a serious problem in military and civilian sectors. Through the Restoring Active Memory program, DARPA aims to better understand the underlying neurological basis of memory loss and speed the development of innovative therapies.”

Specifically, RAM performers aim to develop and test wireless, fully implantable neural-interface medical devices that can serve as “neuroprosthetics”—technology that can effectively bridge the gaps that interfere with an individual’s ability to encode new memories or retrieve old ones.

To start, DARPA will support the development of multi-scale computational models with high spatial and temporal resolution that describe how neurons code declarative memories—those well-defined parcels of knowledge that can be consciously recalled and described in words, such as events, times, and places. Researchers will also explore new methods for analysis and decoding of neural signals to understand how targeted stimulation might be applied to help the brain reestablish an ability to encode new memories following brain injury. “Encoding” refers to the process by which newly learned information is attended to and processed by the brain when first encountered.

Building on this foundational work, researchers will attempt to integrate the computational models developed under RAM into new, implantable, closed-loop systems able to deliver targeted neural stimulation that may ultimately help restore memory function. These studies will involve volunteers living with deficits in the encoding and/or retrieval of declarative memories and/or volunteers undergoing neurosurgery for other neurological conditions.

Unique to the UCLA team’s approach is a focus on the portion of the brain known as the entorhinal area. UCLA researchers previously demonstrated that human memory could be facilitated by stimulating that region, which is known to be involved in learning and memory. Considered the entrance to the hippocampus—which helps form and store memories—the entorhinal area plays a crucial role in transforming daily experience into lasting memories. Data collected during the first year of the project from patients already implanted with brain electrodes as part of their treatment for epilepsy will be used to develop a computational model of the hippocampal-entorhinal system that can then be used to test memory restoration in patients.

After developing an advanced, new wireless neuromodulation device—featuring ten-times smaller size and much higher spatial resolution than existing devices—the UCLA team will implant such devices into the entorhinal area and hippocampus of patients with traumatic brain injury.

The Penn team’s approach is based on an understanding that memory is the result of complex interactions among widespread brain regions. Researchers will study neurosurgical patients who have electrodes implanted in multiple areas of their brains for the treatment of various neurological conditions. By recording neural activity from these electrodes as patients play computer-based memory games, the researchers will measure “biomarkers” of successful memory function—patterns of activity that accompany the successful formation of new memories and the successful retrieval of old ones. Researchers could then use those models and a novel neural stimulation and monitoring system—being developed in partnership with Medtronic—to restore brain memory function. The investigational system will simultaneously monitor and stimulate a number of brain sites, which may lead to better understandings of the brain and how brain stimulation therapy can potentially restore normal brain function following injury or the onset of neuropsychological illness.

In addition to human clinical efforts, RAM will support animal studies to advance the state-of-the-art of quantitative models that account for the encoding and retrieval of complex memories and memory attributes, including their hierarchical associations with one another. This work will also seek to identify any characteristic neural and behavioral correlates of memories facilitated by therapeutic devices.

Learn Dutch in your sleep

When you have learned words in another language, it may be worth listening to them again in your sleep. A study funded by the Swiss National Science Foundation (SNSF) has now shown that this method reinforces memory.

​Reluctant students and sleepyheads take note: a study conducted at the universities of Zurich and Fribourg has shown that German-speaking students are better at remembering the meaning of newly learned Dutch words when they hear the words again in their sleep. “Our method is easy to use in daily life and can be adopted by anyone,” says study director and biopsychologist Björn Rasch. However, the results were obtained in strictly controlled laboratory conditions. It remains to be seen whether they can be successfully transferred to everyday situations.

Quiet playback

In their trial, which has been published in the journal “Cerebral Cortex”, Thomas Schreiner and Björn Rasch asked 60 volunteers to learn pairs of Dutch and German words at ten o’clock in the evening. Half of the volunteers then went to bed. While they slept, some of the Dutch words they had learned before going to bed were played back quietly enough not to awaken them. The remaining volunteers stayed awake to listen to the Dutch words on the playback.

The scientists awoke the sleeping volunteers at two in the morning, then tested everyone’s knowledge of the new words a little later. The group that had been asleep were better at remembering the German translations of the Dutch words they had heard in their sleep. The volunteers who had remained awake were unable to remember words they had heard on the playback any better than those they had not.

Reinforcement of spontaneous activation

Schreiner and Rasch believe that their results provide further evidence that sleep helps memory, probably because the sleeping brain spontaneously activates previously learned subject matter. Playing this subject matter back during sleep can reinforce this activation process and thus improve recall. For example, a person who plays a memory card game to the scent of roses, and is then re-exposed to the same scent while asleep, is subsequently better at remembering where a particular card is in the stack, as Rasch was able to show in another study a few years ago.

Schreiner and Rasch have now observed the beneficial effect of sleep on learning foreign words. A certain amount of swotting is still needed, though. “You can only successfully activate words that you have learned before you go to sleep. Playing back words you don’t know while you’re asleep has no effect,” says Schreiner.

The secrets of children’s chatter: research shows boys and girls learn language differently

Experts believe language uses both a mental dictionary and a mental grammar. The mental ‘dictionary’ stores sounds, words and common phrases, while mental ‘grammar’ involves the real-time composition of longer words and sentences. For example, making a longer word ‘walked’ from a smaller one ‘walk’.

However, most research into understanding how these processes work has been carried out with adults.

“Most researchers agree that the way we use language in our minds involves both storing and real-time composition,” said lead researcher Dr Cristina Dye, a specialist in child language development at Newcastle University. “But a lot of the specifics about how this happens are unclear, such as identifying exactly which parts of language are stored and which are composed.

“Most research on this topic has concentrated on adults and we wanted to see if studying children could help us learn more about these processes.”

A test based around 29 irregular verbs and 29 regular verbs was presented to the young participants. Only verbs which would be known by eight-year-olds were used.

They were presented with two sentences. One featured the verb in the context of the sentence, with the second sentence containing a blank to allow the children to produce the past-tense form. For example: Every day I walk to school. Just like every day, yesterday I ____ to school.

The children were asked to produce the missing word as quickly and as accurately as possible and their response times were recorded. The results were then analysed to discover which words were stored or created in real-time.

Results showed girls were more likely to memorise words and phrases – use their mental dictionary - while boys used mental grammar - i.e assembled these from smaller parts - more often.

The findings could have implications in the way youngsters are taught in the classroom, believes Dr Dye, who is based in the Centre for Research in Linguistics and Language Sciences.

She said: “What we found as we carried out the study was that girls were far more likely to remember forms like ‘walked’ while boys relied much more on their mental grammar to compose ‘walked’ from ‘walk’ and ‘ed’. This fits in with previous research which has identified differences between the sexes when it comes to memorising facts and events, where girls also seem to have an advantage compared to boys.

“One interesting aside to this is that as girls often outperform boys at school, it could be that the curriculum is put together in a way which benefits the way girls learn. It may be worth further investigation to see if this is the case and if so, is there a way lessons could be changed so boys can get the most out of them too.”

Paper: Children’s Computation of Complex Linguistic Forms: A study of Frequency and Imageability Effects

(Image: Getty Images)

Little or poor sleep may be associated with worse brain function when aging

Research published today in PLOS ONE by researchers at the University of Warwick indicates that sleep problems are associated with worse memory and executive function in older people.

Analysis of sleep and cognitive (brain function) data from 3,968 men and 4,821 women who took part in the English Longitudinal Study of Ageing (ELSA), was conducted in a study funded by the Economic and Social Research Council (ESRC). Respondents reported on the quality and quantity of sleep over the period of a month.

The study showed that there is an association between both quality and duration of sleep and brain function which changes with age.

In adults aged between 50 and 64 years of age, short sleep (<6hrs per night) and long sleep (>8hrs per night) were associated with lower brain function scores. By contrast, in older adults (65-89 years) lower brain function scores were only observed in long sleepers.

Dr Michelle A Miller says “6-8 hours of sleep per night is particularly important for optimum brain function, in younger adults”. These results are consistent with our previous research, which showed that 6-8 hours of sleep per night was optimal for physical health, including lowest risk of developing obesity, hypertension, diabetes, heart disease and stroke”.

Interestingly, in the younger pre-retirement aged adults, sleep quality did not have any significant association with brain function scores, whereas in the older adults (>65 years), there was a significant relationship between sleep quality and the observed scores.

“Sleep is important for good health and mental wellbeing” says Professor Francesco Cappuccio, “Optimising sleep at an older age may help to delay the decline in brain function seen with age, or indeed may slow or prevent the rapid decline that leads to dementia”.

Dr Miller concludes that “if poor sleep is causative of future cognitive decline, non-pharmacological improvements in sleep may provide an alternative low-cost and more accessible Public Health intervention, to delay or slow the rate of cognitive decline”.

Study finds that learning by repetition impairs recall of details

When learning, practice doesn’t always make perfect.

UC Irvine neurobiologists Zachariah Reagh and Michael Yassa have found that while repetition enhances the factual content of memories, it can reduce the amount of detail stored with those memories. This means that with repeated recall, nuanced aspects may fade away.

In the study, which appears this month in Learning & Memory, student participants were asked to look at pictures either once or three times. They were then tested on their memories of those images. The researchers found that multiple views increased factual recall but actually hindered subjects’ ability to reject similar “imposter” pictures. This suggests that the details of those memories may have been shaken loose by repetition.

This discovery supports Reagh’s and Yassa’s Competitive Trace Theory – published last year in Frontiers in Behavioral Neuroscience – which posits that the details of a memory become more subjective the more they’re recalled and can compete with bits of other similar memories. The scientists hypothesize that this may even lead to false memories, akin to a brain version of the telephone game.

Yassa, an assistant professor of neurobiology & behavior, said that these findings do not discredit the practice of repetitive learning. However, he noted, pure repetition alone has limitations. For a more enriching and lasting learning experience through which nuance and detail are readily recalled, other memory techniques should be used to complement repetition.

Stress hormone linked to short-term memory loss as we age

A new study at the University of Iowa reports a potential link between stress hormones and short-term memory loss in older adults.

The study, published in the Journal of Neuroscience, reveals that having high levels of cortisol—a natural hormone in our body whose levels surge when we are stressed—can lead to memory lapses as we age.

Short-term increases in cortisol are critical for survival. They promote coping and help us respond to life’s challenges by making us more alert and able to think on our feet. But abnormally high or prolonged spikes in cortisol—like what happens when we are dealing with long-term stress—can lead to negative consequences that numerous bodies of research have shown to include digestion problems, anxiety, weight gain, and high blood pressure.

In this study, the UI researchers linked elevated amounts of cortisol to the gradual loss of synapses in the prefrontal cortex, the region of the brain that houses short-term memory. Synapses are the connections that help us process, store, and recall information. And when we get older, repeated and long-term exposure to cortisol can cause them to shrink and disappear.

“Stress hormones are one mechanism that we believe leads to weathering of the brain,” says Jason Radley, assistant professor in psychology at the UI and corresponding author on the paper. Like a rock on the shoreline, after years and years it will eventually break down and disappear.

While previous studies have shown cortisol to produce similar effects in other regions of the aging brain, this was the first study to examine its impact on the prefrontal cortex.

And although preliminary, the findings raise the possibility that short-memory decline in aging adults may be slowed or prevented by treatments that decrease levels of cortisol in susceptible individuals, says Radley. That could mean treating people who have naturally high levels of cortisol—such as those who are depressed—or those who experience repeated, long-term stress due to traumatic life events like the death of a loved one.

According to Radley and Rachel Anderson, the paper’s lead author and a second year-graduate student in psychology at the UI, short-term memory lapses related to cortisol start around age 65. That’s about the equivalent of 21 month-old rats, which the pair studied to make their discovery.

The UI scientists compared the elderly rats to four-month old rats, which are roughly the same age as a 20 year-old person. The young and elderly groups were then separated further according to whether the rats had naturally high or naturally low levels of corticosterone—the hormone comparable to cortisol in humans.

The researchers subsequently placed the rats in a T-shaped maze that required them to use their short-term memory. In order to receive a treat, they needed to recall which direction they had turned at the top of the T just 30, 60, or 120 seconds ago and then turn the opposite way each time they ran the maze.

Though memory declined across all groups as the time rats waited before running the maze again increased, older rats with high corticosterone levels consistently performed the worst. They chose the correct direction only 58 percent of the time, compared to their older peers with low corticosterone levels who chose it 80 percent of the time.

When researchers took tissue samples from the rats’ prefrontal cortexes and examined them under a microscope, they found the poor performers had smaller and 20 percent fewer synapses than all other groups, indicating memory loss.

In contrast, older rats with low corticosterone levels showed little memory loss and ran the maze nearly as well as the younger rats, who were not affected by any level of corticosterone—low or high.

Still, researchers say it’s important to remember that stress hormones are only one of a host of factors when it comes to mental decline and memory loss as we age.