Tobacco-Derived Compound Prevents Memory Loss in Alzheimer's Disease Mice

ScienceDaily (Apr. 28, 2011) — Cotinine, a compound derived from tobacco, reduced plaques associated with dementia and prevented memory loss in a mouse model of Alzheimer's disease, a study led by researchers at Bay Pines VA Healthcare System and the University of South Florida found.

The findings are reported online in the Journal of Alzheimer's Disease in advance of print publication.

"We found a compound that protects neurons, prevents the progression of Alzheimer's disease pathology, enhances memory and has been shown to be safe," said Valentina Echeverria, PhD, a scientist at Bay Pines VA Healthcare System and an assistant professor of Molecular Medicine at USF Health. "It looks like cotinine acts on several aspects of Alzheimer's pathology in the mouse model. That, combined with the drug's good safety profile in humans, makes it a very attractive potential therapy for Alzheimer's disease."

While the current drugs for Alzheimer's may help delay the onset of symptoms, none halt or reverse the processes of Alzheimer's disease. In addition, existing drugs may have undesirable side effects.

Some epidemiological studies showed that people who smoke tend to have lower incidences of Parkinson's disease and Alzheimer's disease. Studies have widely attributed this apparently beneficial effect to nicotine, which has been reported to improve memory and reduce Alzheimer's-like plaques in mice. However, nicotine's harmful cardiovascular effects and addictive properties make the compound a less than ideal drug candidate for neurodegenerative diseases.

The Bay Pines VA/USF team decided to look at the effects of cotinine, the major byproduct of nicotine metabolism, in Alzheimer's disease mice. Cotinine is nontoxic and longer lasting than nicotine. Furthermore, its safety has already been demonstrated in human trials evaluating cotinine's potential to relieve tobacco withdrawal symptoms.

The researchers administered cotinine daily for five months to young adult (2-month-old) mice genetically altered to develop memory problems mimicking Alzheimer's disease as they aged. At the end of the five-month study, the Alzheimer's mice treated with cotinine performed better on tasks measuring their working memory and thinking skills than untreated Alzheimer's control mice. Long-term cotinine treatment appeared to provide the Alzheimer's mice complete protection from spatial memory impairment; their performance in this area of testing was identical to that of normal mice without dementia.

The brains of Alzheimer's mice treated with cotinine showed a 26-percent reduction in deposits of amyloid plaques, which are a hallmark of Alzheimer's disease. Cotinine also inhibited the accumulation of the amyloid peptide oligomers -- a predecessor of senile plaques -- in the brains of these mice. Furthermore, the researchers discovered that cotinine stimulated the signaling factor Akt, which promotes the survival of neurons and enhances attention and memory.

Senile plaques likely had not yet formed or were just beginning to accumulate in the brains of the young adult mice when long-term cotinine treatment was started. The researchers suggest that "cotinine may be useful in preventing cognitive deterioration when administered to individuals not yet exhibiting Alzheimer's disease cognitive impairment or those with mild cognitive impairment at early stages of the disease."

The researchers are seeking additional support for a pilot clinical trial to investigate cotinine's effectiveness in preventing progression to Alzheimer's dementia in patients with mild cognitive impairment, Echeverria said.

The VA-USF team is also studying the potential of the tobacco-derived compound to relieve fear-induced anxiety and help blunt traumatic memories in mouse models of post-traumatic stress disorder.

Study co-authors included researchers from the University of Miami, the University of Manchester (UK), Boston College, and Saitama Medical Center and Saitama Medical University (Japan). The study was supported in part by awards from the Florida Department of Health's James and Esther King Biomedical Research Program, the Alzheimer's Association and the Japan Society for the Promotion of Science.

Can Traumatic Memories Be Erased?

ScienceDaily (Apr. 28, 2011) — Could veterans of war, rape victims and other people who have seen horrific crimes someday have the traumatic memories that haunt them weakened in their brains? In a new study, UCLA life scientists report a discovery that may make the reduction of such memories a reality.

Could veterans of war, rape victims and other people who have seen horrific crimes someday have the traumatic memories that haunt them weakened in their brains? In a new study, UCLA life scientists report a discovery that may make the reduction of such memories a reality. "I think we will be able to alter memories someday to reduce the trauma from our brains," said the study's senior author

"I think we will be able to alter memories someday to reduce the trauma from our brains," said the study's senior author, David Glanzman, a UCLA professor of integrative biology and physiology and of neurobiology.

The study appears in the April 27 issue of the Journal of Neuroscience.

Glanzman, a cellular neuroscientist, and his colleagues report that they have eliminated, or at least substantially weakened, a long-term memory in both the marine snail known as Aplysia and neurons in a Petri dish. The researchers say they gaining important insights into the cell biology of long-term memory.

They discovered that the long-term memory for sensitization in the marine snail can be erased by inhibiting the activity of a specific protein kinase -- a class of molecules that modifies proteins by chemically adding to them a phosphate (an inorganic chemical), which changes the proteins' structure and activity. The protein kinase is called PKM (protein kinase M), a member of the class known as protein kinase C (PKC), which is associated with memory.

The research has important potential implications for the treatment of post-traumatic stress disorder, as well as drug addiction, in which memory plays an important role, and perhaps Alzheimer's disease and other long-term memory disorders.

"Almost all the processes that are involved in memory in the snail also have been shown to be involved in memory in the brains of mammals," said Glanzman, who added that the human brain is far too complicated to study directly.

PKM is rare in that while most protein kinases have both a catalytic domain, which is the part of the molecule that does its work, and a regulatory domain, akin to an on-off switch that can be used by other signaling pathways to shut off the activity of the kinase, PKM has only the catalytic domain -- not the regulatory domain.

"This means that once PKM is formed, there is no way to shut it off," said Glanzman, who is a member of UCLA's Brain Research Institute. "Once it is activated, PKM's continual activity maintains a memory until PKM degrades."

Glanzman decided to study PKM in the marine snail, which has simple forms of learning and a simple nervous system, so that he could understand in precise detail how PKM's activity maintains a long-term memory, a process that is not well understood.

Glanzman and his colleagues -- researchers Diancai Cai, lead author of the study; Kaycey Pearce; and Shanping Chen, all of whom work in his laboratory -- studied a simple kind of memory called sensitization. If marine snails are attacked by a predator, the attack heightens their sensitivity to environmental stimuli -- a "fundamental form of learning that is necessary for survival and is very robust in the marine snail," Glanzman said.

"The advantage of Aplysia," he said, "is that we know the neurons that produce this reflex; we know where they are in the nervous system."

The scientists removed the key neurons from the snail's nervous system and put them in a Petri dish, thereby recreating in the dish the two-neuron "circuit" -- a sensory neuron and a motor neuron -- that produces the reflex.

"The point is to reduce the problem so we can study on a fundamental biological level how PKM is maintaining long-term memory," Glanzman said.

They succeeded in erasing a long-term memory, both in the snail itself and in the circuit in the dish. They are the first scientists to show that long-term memory can be erased at a connection between just two neurons.

"We found that if we inhibit PKM in the marine snail, we will erase the memory for long-term sensitization," Glanzman said. "In addition, we can erase the long-term change at a single synapse that underlies long-term memory in the snail."

The scientists administered electric shocks to the snails' tails. Following this training, when the scientists gently touched a snail's siphon (an organ in their mid-section used in respiration), the animal responded with a reflexive contraction that lasted about 50 seconds. A week later, when the scientists touched the siphon, the reflex still lasted 30 seconds or more, rather than just the second or two the reflex normally lasts without the shock training. This constituted a long-term memory.

Then, once the marine snail had formed the long-term memory, the scientists injected an inhibitor of PKM into the snail and 24 hours later touched the siphon; the marine snail responded as though it had never received the tail shocks, with a very brief contraction.

"The long-term memory is gone," Glanzman said.

Life scientists agree that learning is due to changes in the synaptic connections, some of which strengthen and some of which weaken, in the brain. This new research opens the door to learning how the changes in synaptic connections are maintained and what role PKM plays in this memory maintenance. Glanzman and his colleagues are now conducting detailed analyses.

During the long-term memory, new synaptic connections grow between the sensory neuron and the motor neuron. If the scientists inhibit PKM, will those synaptic connections disappear?

"We're going to study that," Glanzman said. "Now we can study the cell biology of how PKM maintains long-term memory. Once we know that, we may be able to alter long-term memories. This has implications for psychiatric disorders that are related to memory. Post-traumatic stress disorder is a hyper-induction of a long-term memory that won't go away."

Targeting specific memories

Is there a way to turn the traumatic memory down?

"This is the first step toward figuring that out," Glanzman said. "Even after we know this, we will still need a way to target the memory. We have captured the memory in the dish, but we also have to know where in the brain the memory is."

Does he think it will become possible to target and weaken specific traumatic memories?

"I do," Glanzman said. "Not in the immediate future, but I think we will be able to go into one's brain, identify the location of the memory of a traumatic experience and try to dampen it down. We can do this in culture, and there is no essential difference between the synapse in culture and the synapse in your brain. We have captured the memory in the dish; now we have to figure out a way to target the memories in human brains. Once we know the neural circuit that contains the memory, then we need a selective way to inhibit the activity of PKM in that circuit."

People have different brain circuits -- collections of neurons and synapses that join neurons -- for different memories, Glanzman believes. Scientists may seek to inhibit PKM in a particular circuit. The goal would be to find the brain circuit that is predominantly associated with a traumatic memory and target PKM in that circuit.

If you boost rather than inhibit PKM activity, might that have a beneficial affect for patients with Alzheimer's disease? Alzheimer's disease appears to initially disrupt the synaptic basis of learning, Glanzman said, and PKM might be involved in that disruption.

Just as scientists are seeking to target and kill cancer cells without damaging healthy cells, Glanzman intends to study whether it is possible to weaken only certain synapses associated with traumatic memories, while leaving other memories intact.

"The brain is the most complicated organ in the body," Glanzman said, noting that the brain has many trillions of synapses. "The research is complex, but this is the way we are going to understand how memories in our brains last a lifetime, or at least part of the way. It will take a lot of research, but I think it will be feasible."

Next steps include studying the relationship between PKM and the synapses and how the structure of synapses changes when PKM is inhibited.

"That is going to tell us how long-term memories are maintained," Glanzman said. "This is the first step. The more we know about how long-term memory is induced in the brain and how our memories are maintained in the brain, the more we are going to be able to treat long-term memory loss."

The experiments are very difficult, and Glanzman praised co-authors Cai, Pearce and Chen as "unbelievably skilled."

For 28 years, Glanzman has studied learning and memory in the marine snail, which is substantially larger than its garden variety counterpart and has approximately 20,000 neurons in its central nervous system; humans have approximately 1 trillion. However, the cellular and molecular processes seem to be very similar between the marine snail and humans.

"The fundamental mechanisms of learning and memory are identical, as far as we can tell," Glanzman said.

Glanzman's research is funded by a Senator Jacob Javits Award in the Neurosciences from the National Institute of Neurological Disorders and Stroke (NINDS) and by the National Institute of Mental Health.

The marine snail processes information about its environment and is capable of learning when an environment is safe and when it is not, learning to escape from predators, and learning to identify food. The marine snail is native to California, living in tidal waters off the coast.

Glanzman is also studying learning at the synaptic level in the zebra fish.

In earlier research, Glanzman's team identified a cellular mechanism in the Aplysia that plays an important role in learning and memory. A protein called the NMDA (N-methyl D-aspartate) receptor enhances the strength of synaptic connections in the nervous system and plays a vital role in memory and in certain kinds of learning in the mammalian brain as well. Glanzman's demonstration that the NMDA receptor plays a critical role in learning in the marine snail was entirely unexpected.

Mutations in Single Gene May Have Shaped Human Cerebral Cortex

ScienceDaily (Apr. 28, 2011) — The size and shape of the human cerebral cortex, an evolutionary marvel responsible for everything from Shakespeare's poetry to the atomic bomb, are largely influenced by mutations in a single gene, according to a team of researchers led by the Yale School of Medicine and three other universities.

An MRI of brain of patient with severe form of microcephaly compared to a control subject. A team of researchers have found that mutations in a single gene may cause large discrepancy in size of the cerebral cortex.

The findings, reported April 28 in theAmerican Journal of Human Genetics, are based on a genetic analysis of in one Turkish family and two Pakistani families with offspring born with the most severe form of microcephaly. The children have brains just 10 percent of normal size. They also lacked the normal cortical architecture that is a hallmark of the human brain. This combination of factors has not been seen in other genes associated with the development of the human brain, the authors note.

The researchers found that mutations in the same gene, centrosomal NDE1, which is involved in cell division, were responsible for the deformity.

"The degree of reduction in the size of the cerebral cortex and the effects on brain morphology suggest this gene plays a key role in the evolution of the human brain," said Murat Gunel, co-senior author of the paper and the Nixdorff-German Professor of Neurosurgery and professor of genetics and neurobiology at Yale.

Scientists from Yale, the University of Cambridge, Harvard and Northwestern universities collaborated on the study with colleagues around the world, including those in Turkey and Saudi Arabia.

"These findings demonstrate how single molecules have influenced the expansion of the human cerebral cortex in the last five million years," Gunel said. "We are now a little closer to understanding just how this miracle happens."

The research was funded by the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, the National Institutes of Health and the Wellcome-Trust.

Mehmet Bakircioglu of Yale was co-first author of the paper. Other Yale authors on the paper are Tanyeri Barak, Saliha Yilmaz, Okay Caglayan and Kaya Bilguvar.

Electrical Oscillations Found to Be Critical for Storing Spatial Memories in Brain

ScienceDaily (Apr. 28, 2011) — Biologists at UC San Diego have discovered that electrical oscillations in the brain, long thought to play a role in organizing cognitive functions such as memory, are critically important for the brain to store the information that allows us to navigate through our physical environment.

Red dots signal the location of electrical impulses generated within this grid cell, which are needed for the brain to store information about the rat's physical environment.

The scientists report in the April 29 issue of the journal Science that neurons called "grid cells" that create maps of the external environment in one portion of our brain require precisely timed electrical oscillations in order to function properly from another part of the brain that serves as a kind of neural pacemaker.

Their discovery has important implications for understanding the underlying causes of neurological diseases such as Alzheimer's disease and for restoring memory in areas of the brain that are necessary for orientation.

"This work is the first to demonstrate that oscillatory activity has a well-defined function in brain areas that store memories," says Stefan Leutgeb, an assistant professor of biology at UCSD who headed the team of researchers.

Scientists have long known that among the first brain areas to degenerate in Alzheimer's disease, leading to symptoms such as memory loss and disorientation, are the hippocampus and the nearby entorhinal cortex, important structures for the formation of memory. Those two regions of the brain contain three types of neurons that contribute to the formation of spatial memories and the spatial information in episodic memories from our life experiences.

These three types of neurons provide an internal GPS system to the brain. For example, one type of neuron, called "place cells," generates electrical activity only when an animal is at a certain position, while another type, called "head direction cells," acts like a compass. A third class of neurons, called "grid cells," provides grid-like patterns for the brain to store memories of physical dimensions of the external environment. The most striking feature about these cells is that their electrical activity is distributed at equidistant, periodic locations within each cell (shown in the image). Grid cells were discovered by Norwegian scientists in rats in 2005, but in 2010 researchers in London detected groups of cells in human entorhinal cortex that share the same characteristics.

Leutgeb and his team of UCSD biologists -- postdoctoral researcher Julie Koenig, undergraduate student Ashley Linder and Jill Leutgeb, an assistant professor of biology -- were motivated to understand the function of electrical oscillations in the brain, which are routinely measured in clinical settings to diagnose neurological disorders.

Leutgeb's group demonstrated that neurons called grid cells in the entorhinal cortex that create maps of the external environment require precisely timed electrical oscillatory input signals from a neural pacemaker in the subcortex of the brain to function properly.

"Our findings represent a major milestone in understanding memory processing, and they will guide efforts to restore memory function when cells in the entorhinal cortex are damaged," says Stefan Leutgeb.

A group of scientists from Boston University reports related findings in a companion paper in the same April 29th issue of Science.

The UCSD researchers monitored the electrical activity of grid cells in rats that explored a small four-foot by four-foot enclosure. Grid cells, located in the entorhinal cortex just adjacent to the hippocampus, maintain an internal representation of the external environment. This representation is a grid-like map made of repeating equilateral triangles that tile the space in a hexagonal pattern. As an animal navigates through its environment, a given grid cell becomes active when the animal's position coincides with any of the vertices within the grid.

The scientists silenced the oscillatory input by manipulating a small group of pacemaker cells in the brain and observed a significant deterioration of the grid cells' maps of the environment.

Surprisingly, silencing the oscillatory input did not disrupt brain signals that indicate precise location (provided by place cells) and the compass signal (provided by head direction cells).

"It has been thought that the hippocampus is under control of the entorhinal cortex, so there was the assumption that grid cells would have a very large impact on place cells. We are surprised at how the function of place cells is maintained in the face of significant disruption in grid cell function," says Leutgeb.

"This important result shows that, in general, you can eliminate a substantial amount of incoming information to a brain circuit without that brain circuit losing a majority of its functionality," he adds. "The implication of this finding is that restoring memory function does not require that we exactly reassemble damaged neural circuitry, rather we can regain function by preserving or restoring key components."

"Our findings are a major step towards identifying these key components in an effort to preserve memory function in aging individuals and in patients with neurodegenerative diseases," he says.

The research project was supported by grants from the National Science Foundation, the National Institutes of Health, the Ellison Medical Foundation and the Alzheimer's Association.

BOLETIM ELETRÔNICO ABRASCO

Pesquisa em Atenção Primária à Saúde: como construir uma agenda para o Brasil? A Rede de Pesquisa em Atenção Primária à Saúde abriu seu terceiro fórum de debates sobre o tema "Pesquisa em Atenção Primária à Saúde: como construir uma agenda para o Brasil?". A partir da pauta proposta a Rede coloca três questões para reflexão: Considerando-se que a elaboração de uma agenda de pesquisa em APS deve buscar refletir a natureza e complexidade desse objeto, que eixos ou dimensões devem ser priorizados na pesquisa em APS e por quê?; Que iniciativas devem ser implementadas ou fortalecidas para impulsionar o desenvolvimento da pesquisa em APS e qual o protagonismo e tarefas da Rede de Pesquisa em APS nessa questão? e; Como melhorar a utilização dos resultados de pesquisa por gestores e profissionais no âmbito da APS?. O Fórum recebe contribuições até o dia 10 de maio, quando será realizado um debate online, das 16h às 17h, com as coordenadoras da atividade, Maria Guadalupe Medina e Rosana Aquino (Pesquisadoras do Instituto de Saúde Coletiva da Universidade Federal da Bahia, Coordenadoras do Programa Integrado de Pesquisa e Cooperação Técnica em Formação e Avaliação da Atenção Básica - GRAB). Saiba como participar clicando aqui.

Saúde Mental em pauta O coordenador do GT Saúde Mental da ABRASCO e do Laboratório de Estudos e Pesquisas em Saúde Mental e Atenção Psicossocial da Escola Nacional de Saúde Pública Sergio Arouca (Laps/ENSP), Paulo Amarante, um dos organizadores do projeto Loucos pela Diversidade e nome reconhecido no movimento de reforma psiquiátrica no Brasil é o entrevistado da primeira edição da revista eletrônica RapaDura. A entrevista, feita em vídeo, aborda temas como: a situação das instituições psiquiátricas, a forma como o Estado trata a questão e o conceito de alienação, Reforma Manicomial, o SUS, o mercado da saúde, entre outros temas. Confira a entrevista clicandoaqui.

Presidente da SBMFC concede entrevista à Rede de Pesquisa APS Gustavo Gusso, presidente da Sociedade Brasileira de Medicina de Família e Comunidade (SBMFC) é o entrevistado do mês de abril da Rede de Pesquisa em Atenção Primária à Saúde. Na entrevista Gusso fala sobre os pontos positivos e negativos do SUS, e da APS em particular, destacando seus principais avanços e a dificuldade importa pela contratação de profissionais (especialmente médicos), os desafios que enfrenta na presidência da SBMFC, a programação do 11° Congresso Brasileiro de Medicina de Família e as contribuições da Rede de Pesquisa em APS. Confira a entrevista clicando aqui.

´Semana da saúde´ no Senado tem 47 projetos em pauta Um total de 47 projetos pode fazer parte da "semana da saúde", esforço concentrado para votação de projetos da área definido pelo presidente do Senado, José Sarney, em conjunto com lideranças partidárias. A prevenção ao uso de drogas, a relação dos clientes com os planos de atendimento e o custeio e a organização da saúde são temas dominantes nas propostas. Mais detalhes aqui.

Fórum de Mobilização para Enfrentamento das Doenças Negligenciadas O Programa de Enfrentamento às Doenças Negligenciadas da Secretaria de Saúde do Governo de Pernambuco está promovendo o Fórum de Mobilização para Enfrentamento das Doenças Negligenciadas, no próximo dia 05 de maio, das 8h30 às 17h. O encontro tem como objetivo falar sobre o enfrentamento de doenças tropicais endêmicas que atingem a população de baixa renda: tracoma, doença de Chagas, hanseníase, filariose, esquistossomose, helmintíase e tuberculose e será realidado no Centro de Convenções da Universidade Federal de Pernambuco.

Seminário Internacional Rotas Críticas III: situações limite decorrentes de violências de Gênero O Seminário Internacional Rotas Críticas III: situações limite decorrentes de violências de gênero será realizado de 25 a 27 de maio, na Universidade Federal do Rio Grande do Sul. O encontro tem como público alvo a comunidade acadêmica e trabalhadores de saúde, segurança pública, educação, ação social, jurídicos e militantes de ONGs e movimentos sociais. O Seminário é uma promoção da UFRGS, através do Curso de Análise de Políticas e Sistemas de Saúde e do Programa de Pós-graduação em Enfermagem, conta com apoio do CNPq é tem caráter gratuito. Veja a programação detalhada clicando aqui.

10th International Conference on Urban Health We are pleased to announce the call for abstracts for the 10th International Conference on Urban Health (ICUH), to be held November 1–5, 2011 in Belo Horizonte, Brazil. The abstract deadline is June 30th, 2011, and applicants will be notified of the final decisions on their submissions by July 30th.  The website for the Conference is www.icuh2011.com. The principal theme to be addressed will be urban health action toward equity, with special interest in the urban context, its metrics, and interventions. The conference will examine how institutions and governments can develop and implement interventions that improve health equity, based upon the urban health evidence. These issues will be examined in a multitude of sectors, such as climate change, air pollution, physical activity, health services, violence and security, transportation and injuries, housing and infrastructure, neighborhoods and the urban environment, reproductive and maternal child health, the social determinants of health, substance use and vulnerable populations, and still others. The meeting is being jointly organized by the School of Medicine of the Federal University of Minas Gerais (UFMG), the Belo Horizonte Observatory for Urban Health, and the International Society for Urban Health. The Observatory, a partnership between UFMG and the Belo Horizonte Municipality, has made the city a model for efforts to increase health equity in the urban setting. Founded in 2002, its mission is to build workforce capacity in population health research and to conduct urban-themed studies that can drive planning for improving urban health.

Publicações e oportunidades Clique nos links a seguir e confira as publicações e oportunidades da semana.