Los científicos identifican una mutación genética que podría triplicar el riesgo de Alzheimer

Una rara mutación en un gen llamado TREM2 parece casi triplicar el riesgo de enfermedad de Alzheimer en los adultos, halla un estudio reciente.

El TREM2 tiene que ver con las respuestas inmunitarias e inflamatorias, y podría ser otra clave del misterio sobre las causas de la enfermedad de Alzheimer, así como un objetivo para el tratamiento, añadieron los investigadores.

"Hallamos una mutación que confiere un gran riesgo de enfermedad de Alzheimer", apuntó el investigador líder, el Dr. Kari Stefansson, director ejecutivo de deCODE Genetics, con sede en Reikiavik, Islandia.

Aunque apenas un 1.2 por ciento de la población porta la mutación TREM2, cuando se comparó a adultos de 85 o más años de edad con y sin la mutación, los que la portaban tenían casi siete veces más probabilidades de sufrir de enfermedad de Alzheimer, señaló.

Por supuesto, portar esta mutación no significa que la persona esté destinada a desarrollar enfermedad de Alzheimer. El Alzheimer es una enfermedad compleja, y una persona probablemente necesite que se combinen varios factores de riesgo para producir la afección, señaló Stefansson.

"Esto tiene implicaciones para el tratamiento", afirmó. La mutación podría ser un objetivo para nuevos fármacos que suavice su efecto, afirmó.

El informe aparece en la edición en línea del 14 de noviembre de la revista New England Journal of Medicine.

Un experto en Alzheimer elogia el nuevo estudio.

"Esto muestra el valor de la investigación básica", aseguró William Thies, director médico y científico de la Asociación del Alzheimer (Alzheimer's Association). "Este tipo de ciencia es muy importante, y puede acelerar el hallazgo de mejores terapias para la enfermedad de Alzheimer".

Thies anotó que este hallazgo no significa que las personas deban correr a hacerse pruebas de la mutación. En un futuro, la mutación podría ser importante para los tratamientos, pero todavía falta mucho, planteó.

La necesidad de desarrollar tratamientos para el Alzheimer es un tema urgente, añadió.

"El imperativo de hallar nuevas terapias es obvio", enfatizó Thies. "Los datos demográficos sugieren que para mediados de este siglo habrá 15 o 16 millones de personas con la enfermedad, y no podemos cuidar a tanta gente. El trastorno en la sociedad será grave".

Para el estudio, el grupo de Stefansson obtuvo secuencias genéticas de más de 2,200 islandeses. Los investigadores buscaron variantes genéticas entre los que sufrían Alzheimer y los que no.

Para comprobar sus resultados, los investigadores observaron otras poblaciones en Estados Unidos, Noruega, los Países Bajos y Alemania, donde confirmaron los hallazgos.

Otro experto anotó que el hallazgo sobre la inflamación es importante.

"Es de conocimiento común que la inflamación es parte de la patogénesis del Alzheimer", señaló el Dr. Sam Gandy, director asociado del Centro de Investigación sobre la Enfermedad de Alzheimer Mount Sinai, en la ciudad de Nueva York.

Lo que este estudio muestra es que la inflamación es tan importante que un desequilibrio del componente inflamatorio puede afectar el riesgo de la enfermedad, comentó.

"Actualmente no contamos con un nuevo fármaco, pero el TREM2 resalta pasos en la patogénesis del Alzheimer potencialmente susceptibles a los medicamentos que quizás nunca hubiéramos estudiado a no ser por esta información genética", planteó Gandy.

Greg Cole, otro experto y neurocientífico del Sistema de Atención de Salud de VA del área metropolitana de Los Ángeles, así como director asociado del Centro de Investigación sobre la Enfermedad de Alzheimer de la Facultad de Medicina David Geffen de la UCLA, opinó sobre los hallazgos.

Cole dijo que "junto con otros descubrimientos sobre variantes en los genes expresados en la misma población de células inmunitarias, este estudio amplía unos datos que ahora resultan convincentes sobre un rol causal de las células inmunitarias innatas del cerebro en el desarrollo de la enfermedad de Alzheimer, el tipo más común de demencia".

Comprender el rol de las mutaciones genéticas "ayudará a los investigadores a crear fármacos que logren el efecto opuesto y que modulen la función del sistema inmunitario innato para reducir el riesgo", dijo.

Otro estudio en la misma edición de la revista llegó a la misma conclusión.

Un equipo liderado por John Hardy, del Instituto de Neurología del Colegio Universitario de Londres, y por Andrew Singleton, del Instituto Nacional del Envejecimiento (NIA) de EE. UU., también halló que la mutación del TREM2 aumentaba el riesgo de enfermedad de Alzheimer.

"Durante años hemos planteado la hipótesis de que una variante genética rara puede conferir un riesgo moderado de la enfermedad", señaló Singleton en un comunicado del NIA. "Estos son los primeros estudios en identificar una variante de este tipo relacionada con la enfermedad de Alzheimer".

FUENTES: Kari Stefansson, M.D., Ph.D., CEO, deCODE genetics, Reykjavik, Iceland; William Thies, Ph.D., chief medical and scientific officer, Alzheimer's Association; Sam Gandy, M.D., Ph.D., associate director, Mount Sinai Alzheimer's Disease Research Center, New York City; Greg Cole, Ph.D., neuroscientist, Greater Los Angeles VA Healthcare System, and associate director, Alzheimer's Disease Research Center, University of California, Los Angeles, David Geffen School of Medicine; Nov. 14, 2012, news release, U.S. National Institute on Aging; Nov. 14, 2012, New England Journal of Medicine online

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Alzheimers .gov en español

http://www.alzheimers.gov/espanol/

The Answers Start Here (En Español)

Alzheimer de inicio precoz

¿Qué es la enfermedad de Alzheimer de inicio precoz?

La enfermedad de Alzheimer de inicio precoz es cuando el Alzheimer afecta a una persona menor de 65 años. Las personas que padecen de Alzheimer de inicio precoz pueden desarrollar síntomas ya en los 30 o 40 años de edad, pero la mayoría están entre los 50 o 60 años.

¿Qué tan común es el Alzheimer de inicio precoz?

El Alzheimer de inicio precoz no es muy común. Menos del 5 por ciento de las personas que padecen la enfermedad de Alzheimer tienen un inicio precoz.

¿Cómo se diferencia el Alzheimer de inicio precoz del Alzheimer de inicio tardío?

Cuando el Alzheimer comienza, la única diferencia no está entre el inicio precoz y “regular” o inicio tardío. Las otras diferencias incluyen lo siguiente:

• Genética: Los médicos e investigadores han descubierto que, en algunas personas, ciertos genes extraños pueden hacer que los síntomas de Alzheimer comiencen a temprana edad. Cuando la genética es la causa, a menudo los genes se han transmitido a los familiares y pueden afectar a muchas generaciones.  Esta es la razón por la que el Alzheimer de inicio precoz algunas veces se conoce como Alzheimer “hereditario”.
• Diagnóstico: Es probable que para un médico tome más tiempo diagnosticar el Alzheimer de inicio precoz. Aunque los síntomas del Alzheimer de inicio precoz son los mismos síntomas del Alzheimer de inicio tardío, la mayoría de médicos no busca ni sospecha que exista la enfermedad de Alzheimer en personas más jóvenes. Si está teniendo problemas de memoria, asegúrese de hablar con el médico sobre todos los síntomas.
• Sobrellevarlo: Debido a que las personas que padecen Alzheimer de inicio precoz son más jóvenes, es probable que todavía estén criando hijos, que tengan trabajos y que sean activos en la comunidad cuando los síntomas comienzan. Esto puede hacer más difícil tratar con los cambios que la enfermedad de Alzheimer trae a la familia y vida personal. Las personas que padecen la enfermedad de inicio precoz son más propensas a sentirse enojadas, frustradas o deprimidas.

Consejos para vivir con Alzheimer de inicio precoz

Primero, es importante saber que no está solo. La enfermedad de Alzheimer afecta a cada persona de manera distinta, pero hay actividades que puede hacer para permanecer activo e involucrado en su propio cuidado de la salud, con la familia y los amigos y en el trabajo.

Cuídese

• Siga los consejos de su médico sobre la dieta y el ejercicio. Si toma medicamentos, asegúrese de tomar la cantidad correcta en el momento apropiado. Visite o hable con el médico si tiene preguntas sobre su salud o tratamiento.
• Piense en unirse a un grupo de apoyo. Para encontrar uno cerca de usted, comuníquese con el club local de la Asociación del Alzheimer.
• Comparta sus pensamientos y sentimientos con los demás. No guarde todo eso adentro. Si no se siente cómodo hablando con su familia o amigos, siempre podrá hablar con su médico, miembros de la iglesia o con un terapeuta profesional.

Sea honesto con su familia y amigos

• Hable con su cónyuge u otros familiares cercanos sobre sus pensamientos, temores y anhelos. Su familia puede ayudarle a planificar el futuro, incluso a tomar decisiones sobre el cuidado de la salud, así como acerca de asuntos legales y financieros.
• Hable francamente con sus hijos sobre su enfermedad. Comprenda que es posible que estén preocupados, confundidos, molestos o asustados. Si es adecuado, deje que sus hijos participen en las discusiones y decisiones que afectan a toda la familia.
• Es probable que sus amigos o vecinos no sepan cómo reaccionar a su diagnóstico. Posiblemente sientan que no saben qué decir o cómo ayudar y es probable que esperen a que usted tome la iniciativa. Invite a sus amigos a pasar tiempo con usted. No tenga miedo de pedir ayuda cuando la necesite.

Maneje su carrera profesional

• Tome en cuenta que, mientras los síntomas progresan, es posible que sea difícil realizar ciertas tareas laborales.
• Planifique cuándo y cómo decirle a su jefe, supervisor o gerente.
• Dígale al gerente que le gustaría continuar trabajando tanto como sea posible y pídale que sea flexible. Las posibilidades incluyen trabajar menos horas, reducir las responsabilidades o cambiar de puesto.
• Trabaje con el departamento de recursos humanos para asegurarse de aprovechar todos sus beneficios como empleado. Investigue las opciones de jubilación temprana.

Bibliografía

Forest Laboratories Inc. ha patrocinado este contenido.

Alzheimer’s Association. Younger/Early Onset Alzheimer’s & Dementia. Accessed octubre 17, 2012

Alzheimer’s Association. Living with Younger/Early Onset Alzheimer’s. Accessed octubre 17, 2012

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Delirium Increases Risks in Alzheimer’s Patients

A study of people with Alzheimer’s disease found that a hospital stay greatly increased the risk of further decline, including the need to enter a nursing home and an increased risk of dying. About half of those who were hospitalized also developed delirium, a condition marked by the rapid onset of confusion and disorientation that further amplified the risk of decline and death.

While hospital stays are often needed to treat a variety of medical conditions in people with Alzheimer’s, the findings confirm earlier concerns about the dangers of hospitalization for those with dementia. They also underline the importance of avoiding delirium in Alzheimer’s patients who enter the hospital.

A visit to the hospital is a troubling experience for anyone. The change of environment, constant noise and activity and painful medical procedures can be particularly disorienting for someone with Alzheimer’s disease.

"Our previous research had found that Alzheimer’s patients experienced a three times faster decline in mental function if they had experienced delirium,” said Dr. Tamara Fong of Beth Israel Deaconess Medical Center in Boston, the lead author of the study. “We wanted to determine if Alzheimer’s disease patients who are hospitalized are at greater risk for poor outcomes than Alzheimer’s patients who are not hospitalized, and if there is any additive negative outcome when hospitalized Alzheimer’s patients develop delirium."

The current study, published in the Annals of Internal Medicine, looked at 771 older men and women with Alzheimer’s. Nearly half required a hospital visit within eighteen months of a doctor’s visit, and about half of those developed delirium during their hospital stay.

People who entered the hospital were at almost five-fold increased risk of death compared to those who didn’t require hospitalization, and were at nearly seven times the risk of needing institutional care after their hospital visit. Those who developed delirium were at even higher risk of mental and physical decline, institutionalization and death.

The findings are a good reminder that hospital stays are a precarious time for anyone with Alzheimer’s and should be avoided whenever possible. They also highlight the need to recognize and treat delirium in order to prevent not just short-term problems but also to avoid long-term repercussions that can last for months beyond the hospital stay.

"Evidence has shown that older patients with Alzheimer's disease are much more likely to be hospitalized than other older patients," said Dr. Fong. "Among the hospitalized Alzheimer's patients, a substantial proportion of risk for adverse outcomes could be attributed to delirium, including 6.2 percent of deaths, 15.2 percent of institutionalization, and 20.6 percent of cognitive decline. The bottom line is that delirium can be a big problem for patients with Alzheimer’s disease."

But delirium can often be prevented, Dr. Fong notes. Effective strategies include the Hospital Elder Life Program, or HELP, which is designed to prevent delirium by keeping hospitalized older people oriented to their surroundings, meeting their needs for nutrition, fluids and sleep, and keeping them mobile as much as possible.

"Going forward, we plan to conduct formal studies to determine if these types of interventions can help improve outcomes for this vulnerable group of patients," she explains.

Steps to prevent hospitalizations in the first place are also critical, especially for anyone with Alzheimer’s disease, the authors note.

By ALZinfo.org, The Alzheimer's Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer's Research Foundation at The Rockefeller University.

Source: Tamara G. Fong, MD, PhD; Richard N. Jones, ScD; Edward R. Marcantonio, MD, SM; et al: “Adverse Outcomes After Hospitalization and Delirium in Persons With Alzheimer Disease.” Annals of Internal Medicine, Vol. 156 (No. 12), June 19, 2012, pages 848-856.

How the APOE-E4 Gene May Raise Alzheimer’s Risk...

People who carry the APOE-E4 gene, the most common known genetic contributor to Alzheimer’s, are at increased risk of developing the disease, though having the gene is no guarantee that you’ll get Alzheimer’s. Now scientists are uncovering new clues about how the gene may contribute to Alzheimer’s risk, work that may lead to new approaches to treating the illness.

APOE genes help the body process cholesterol, and people can inherit one of three main forms of the gene from their parents. APOE-E4 is the one that raises Alzheimer’s risk, though it’s important to note that it doesn’t cause the disease. (APOE-E2, the least common form, appears to protect against Alzheimer’s; whereas APOE-E3, the most common form, appears to have no effect on dementia risk.) Carrying one copy of the APOE-E4 gene raises Alzheimer’s risk by two- to three-fold. Carrying two copies of the gene raises the risk by up to 10-fold or more.

Now, researchers at the University of Rochester in New York and the University of Southern California and other medical centers have uncovered new clues about how APOE-E4 may increase Alzheimer’s risk. Through experiments in mice, they found that the APOE-E4 gene appears to cause the blood vessels that feed the brain to “leak,” allowing toxic substances in the bloodstream to infiltrate the brain.

Normally, the blood vessels in the brain are tightly sealed. The resulting blood-brain barrier allows nutrients to enter the brain, and keeps harmful substances out. But in animals that carried the APOE-E4 variant, the same blood vessels were leaky. This process appears to be mediated by a substance called cyclophilin A, levels of which were greatly increased in animals that carried APOE-E4.

"We are beginning to understand much more about how APOE-E4 may be contributing to Alzheimer's disease," said lead author Robert Bell of the University of Rochester. "In the presence of APOE-E4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease.”

Cyclophilin A appears to trigger an inflammatory reaction that weakens the blood-brain barrier. Increasingly, inflammation is recognized as a contributor to Alzheimer’s disease, heart disease and stroke. The process likely begins years before symptoms like memory loss appear.

The current findings, published in the journal Nature, could lead to new approaches to treating Alzheimer’s disease. Developing new drugs that target cyclophilin A, for example, could help to stem the inflammatory cascade that leads to breakdowns in the brain.

"Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer's in late-life,” said Suzana Petanceska of the National Institute on Aging, which helped fund the study. “We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer's."

By ALZinfo.org, The Alzheimer's Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer's Research Foundation at The Rockefeller University.

Source: Robert D. Bell, Ethan A. Winkler, Itender Singh, et al: “Apolipoprotein E Controls Cerebrovascular Integrity via Cyclophilin A.” Nature Vol. 485: Mayy 16, 2012, pages 512-516.

How a Sense of Purpose in Life May Help Slow Alzheimer’s

Having a firm purpose in life may help to dampen the ravages of Alzheimer’s disease, a new study reports. A sense of purpose in life – that believing what you do matters, and that you are doing good and on a meaningful path – has been shown in earlier studies to contribute to greater well-being and better overall health. This latest study showed that it may also help to protect the brain against the damage of Alzheimer’s.

The findings come from Rush University Medical Center in Chicago, where researchers have studied more than 1,500 seniors since 1997. All were free of dementia at the start of the study.

The participants all underwent yearly check-ups and assessments to determine their physical, psychological and cognitive health. To measure how strong their sense of purpose was, they were also asked to rate their reactions to statements like “Some people wander aimlessly through life, but I am not one of them,” and “I feel good when I think what I've done in the past and what I hope to do in the future," responding on a scale of 1 to 5 whether they strongly agree or strongly disagree.

High scorers on the psychological profile of sense of purpose were defined as those who had goals in life and a sense of directedness; felt there is meaning to their present and past life; held beliefs that give life purpose; and had aims and objectives for living.

Low scorers, on the other hand, lacked a sense of meaning in life; had few goals or aims; lacked a sense of direction; did not see the purpose of their past life; and had no outlook or beliefs that gave life meaning.

In the study, 246 participants died, and their brains were autopsied for signs of plaques and tangles, which build up in the brains of those with Alzheimer’s. As plaques and tangles accumulate, memory and thinking skills tend to deteriorate.

But many older people who have relatively large amounts of plaques and tangles in their brains do not develop serious memory problems. One theory is that these individuals may have a high cognitive reserve – an enhanced network of interconnections between brain cells that protects against cognitive decline. If some parts of the brain are damaged by Alzheimer’s, other healthy brain areas may help to compensate for the losses.

The researchers sought to determine whether having a strong purpose might bolster the brain, perhaps by strengthening cognitive reserve. They examined how many plaques and tangles present in in the brains of those who had died, and compared it to how they had scored on their earlier sense of purpose surveys.

Those who scored high on the sense of purpose survey were just as likely as to have plaques and tangles in their brains as those how scored low, the study found. But despite having the same amount of plaques and tangles, those with a strong sense of purpose did tend to score higher on tests of memory and thinking.

“These findings suggest that purpose in life protects against the harmful effects of plaques and tangles on memory and other thinking abilities,” said Patricia Boyle, Ph.D., the lead author of the study, which appeared in the Archives of General Psychiatry. “This is encouraging and suggests that engaging in meaningful and purposeful activities promotes cognitive health in old age.”

While developing a strong sense of purpose is no guarantee that someone will not get Alzheimer’s, it may help. As researchers continue to search for new ways to treat Alzheimer’s and alter its course, any measure that may help to protect the brain may be wise.

By ALZinfo.org, The Alzheimer's Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer's Research Foundation at The Rockefeller University.

Hallan señales de Alzheimer en los cerebros de adultos jóvenes

Un pequeño estudio de una rara forma de la enfermedad incluyó a personas de 18 a 26 años de edad

Unos científicos han descubierto la evidencia más temprana conocida de Alzheimer en personas que portan una mutación genética que provoca una forma de la enfermedad que se inicia a una edad temprana.

Los hallazgos de los dos estudios podrían mejorar la comprensión sobre cómo y por qué el Alzheimer avanza, y posiblemente llevar a una detección más temprana de la enfermedad y a mejores tratamientos, según los investigadores.

En un estudio, los investigadores realizaron escáneres cerebrales y otras pruebas en 44 adultos jóvenes de 18 a 26 años de edad, en Columbia. Veinte de ellos portaban una mutación en un gen llamado presenilina 1 (PSEN1) que hace que el Alzheimer se desarrolle a una edad inusualmente temprana, y 24 no portaban la mutación. Ninguno de los participantes mostraba señales de declive mental en el momento en que se realizó el estudio.

Hubo diferencias notables en la estructura y la función cerebrales entre los adultos jóvenes con la mutación en el PSEN1 y los que no la portaban. Los participantes con la mutación PSEN1 tenían una mayor actividad en unas regiones del cerebro conocidas como hipocampo y parahipocampo, y menos materia gris en ciertas áreas del cerebro.

Además, el líquido cefalorraquídeo de los adultos jóvenes con la mutación PSEN1 tenía niveles más altos de la proteína beta amiloidea, que es un componente de las placas amiloideas del cerebro que se asocian con la enfermedad de Alzheimer.

En promedio, las personas con la mutación PSEN1 comienzan a mostrar síntomas de declive mental a los 45 años. Este estudio muestra que, en estas personas, los biomarcadores son evidentes al menos veinte años antes de la aparición de los primeros síntomas. Eso es antes de lo que ha hallado cualquier otro estudio anterior.

El estudio aparece en la edición del 5 de noviembre de la revista The Lancet Neurology.

"Estos hallazgos sugieren que los cambios cerebrales podrían comenzar muchos años antes del inicio clínico de la enfermedad de Alzheimer, e incluso antes del inicio de la deposición de placas amiloideas. Plantean nuevas preguntas sobre los cambios cerebrales más precoces que tienen que ver con la predisposición al Alzheimer, y hasta qué grado podrían ser intervenidos mediante terapias preventivas futuras", comentó en un comunicado de prensa de la revista el líder del estudio, el Dr. Eric Reiman, del Instituto Banner de Alzheimer, en Arizona.

En un segundo estudio, el mismo grupo de investigadores halló que las placas amiloideas comenzaban a acumularse en los cerebros de las personas que portaban la mutación PSEN1 a finales de la veintena.

Los hallazgos "ayudarán a preparar el terreno para la evaluación de tratamientos para prevenir la enfermedad de Alzheimer familiar, y con algo de suerte ayudarán a nuestra comprensión de las primeras etapas de la enfermedad de Alzheimer de inicio tardío, que es más común", escribieron los investigadores en el informe.

Nick Fox, profesor del Instituto de Neurología del Colegio Universitario de Londres, escribió un comentario en la revista que acompañó al primer estudio.

"Estos hallazgos ponen en duda varios aspectos de nuestros modelos sobre la enfermedad de Alzheimer. Sugieren que los cambios neurodegenerativos ocurren más de veinte años antes del inicio de los síntomas, y un poco antes de lo que sugerían estudios anteriores de imágenes cerebrales de individuos en riesgo de enfermedad de Alzheimer hereditaria", escribió Fox.

"Se necesita más investigación, pero una interpretación de estos resultados podría ser que añaden a la evidencia creciente de que la enfermedad de Alzheimer se caracteriza por un largo periodo presintomático de cambios lentamente progresivos que pueden potencialmente ser rastreados, abriendo así una ventana terapéutica para una intervención temprana", añadió.

FUENTE: The Lancet Neurology, news release, Nov. 5, 2012

Alzinfo - Dr. Victor Bustos

Dr. Victor Bustos: I’m investigating why Alzheimer’s disease appears when people get older. There is a protein in nerve cells called presenilin that undergoes changes with aging. I think some of these changes could explain why aging is the main risk factor for Alzheimer’s disease. So, the target I’m studying is presenilin.

If you had to sum up your work in a few sentences, what would you say?

Dr. Victor Bustos: I use cells growing in culture and genetically engineered animal models to investigate the changes that occur with aging. One of the things I do is to modify these changes using biochemical and genetic methods. Then, I determine whether the models will get Alzheimer’s disease.

What results have you discovered thus far from your research, or what do you expect to find?

Dr. Victor Bustos: I have discovered a change in the molecule presenilin that I believe is a contributing factor for Alzheimer’s disease in elderly people.

What impact might your work have on Alzheimer’s diagnosis or treatment in the future?

Dr. Victor Bustos: I think it will allow us to find drugs that will target presenilin, or other molecules that are regulated by it. This will block the effects of aging so that Alzheimer’s can be avoided.

What directions can you see your work taking in the future?

Dr. Victor Bustos: I think it will open up new avenues for research into aging and have impact on different diseases that are age-dependent.

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Alzinfo - Dr. Jean-Pierre Roussarie

Dr. Jean-Pierre Roussarie: My approach is slightly different from the usual ones. I am trying to understand why certain brain regions are hit harder than others by Alzheimer’s disease (AD).  In other words, what makes the brain region that controls the formation of recent memories more vulnerable than other brain regions in Alzheimer’s disease, and how can we protect these vulnerable brain regions from the ravages of this disease?

If you had to sum up your work in a few sentences, what would you say?

Dr. Jean-Pierre Roussarie: It is clearly not the whole brain that is affected by AD. At early stages, only regions involved in the formation of new memories stop functioning, while the rest of the brain remains normal. To understand why these regions are particularly vulnerable, we are comparing all the proteins present in vulnerable regions to those present in resistant regions, so that we can pinpoint proteins that cause the vulnerability and proteins that cause resistance.

What have you learned thus far from your research?

Dr. Jean-Pierre Roussarie: We've made a lot of progress. We were able to identify a very small number of proteins that are present only in vulnerable regions and not in resistant regions, as well as proteins present in resistant regions but not in vulnerable regions.  We are now investigating whether these proteins indeed play a major role in causing vulnerability or resistance. We have two approaches, the genetic approach, for which we are collaborating with the renowned Alzheimer’s geneticist Rudy Tanzi, to learn if Alzheimer’s patients have mutations in any of the proteins we have identified. We already have one promising candidate protein that is present at much higher levels in resistant brain regions. 

We recently discovered that certain mutations in this protein are associated with the risk of getting AD. Our other approach is to use animal models. We use the really great tools that the Greengard lab has been developing for many years.  They allow us to manipulate the quantity of proteins in the brain of an animal model in any region we want to study. We plan to change the levels of proteins we have associated with vulnerability to see if brain cells become more or less protected in different animal models of AD. These two approaches will tell us which proteins are the most important for protecting or harming brain cells in AD. The proteins are likely to become very promising new therapeutic targets.

What impact might your work have on Alzheimer’s diagnosis or treatment in the future?

Dr. Jean-Pierre Roussarie: The ultimate goal of our work is to be able to prevent vulnerable cells from degenerating. If we find compounds that protect vulnerable cells, we could manage to stop the progression of Alzheimer’s symptoms if we treat patients very early on with these compounds.

What directions can you see your work taking from here?

Dr. Jean-Pierre Roussarie: We still need to refine our understanding of the vulnerability of specific brain regions in Alzheimer’s disease. Once we find the proteins responsible for vulnerability, the next step is to find drugs that target these proteins. Given the decades of experience of the Greengard lab and the great expertise of its scientists, I am very hopeful that we will achieve our goals.

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Alzinfo - Dr. Karima Bettayeb

Dr. Karima Bettayeb: With Alzheimer’s disease, brain pathology is characterized by two hallmark findings: the presence of amyloid plaques resulting from the aggregation of the toxic protein beta amyloid (Aβ), and in later stages the presence of neurofibrillary tangles composed of the protein, tau. An important step in the process of Aβ formation is the cleavage of the amyloid precursor protein (APP) to release Aβ, a reaction catalyzed by the enzyme gamma-secretase (γ-secretase). Great efforts have been put into the development of γ-secretase inhibitors. But γ-secretase has crucial roles in the body in addition to making Aβ (more than 50 proteins have been identified as substrates). The inhibitors discovered so far also inhibit the maturation of substrates other than APP, some of which are crucial for various biological functions, and, when disturbed, lead to deleterious side effects such as cancer.  Our laboratory discovered that Gleevec (imatinib), an FDA-approved drug, dramatically reduces Aβ levels and we have identified the target protein of Gleevec, which we named gamma-secretase activating protein (GSAP). Importantly, we found that the down-regulation of GSAP potently reduces Aβ in animal models without affecting other important substrates of γ-secretase. The therapeutic targeting of GSAP represents a unique alternative to circumvent the side effects associated with the overall inhibition of γ-secretase function. GSAP when discovered was a protein of unknown function. Since I started my post-doctoral work in the Greengard lab, my aim has been to better understand the function of GSAP and elucidate the mechanism by which GSAP selectively regulates γ-secretase cleavage to activate Aβ production. In order to characterize the biological activity of GSAP we searched for GSAP interacting proteins.

If you had to sum up your work in a few sentences, what would you say?

Dr. Karima Bettayeb: The inhibitors discovered so far against Alzheimer disease, reduce one of the two major hallmarks of AD (Aβ plaques but not tau tangles) by targeting an enzyme called γ-secretase. Unfortunately, these inhibitors have serious adverse side effects, due to a lack of specificity. My project was specifically designed to address this limitation. We discovered that Gleevec dramatically reduces Aβ levels via a protein that we named gamma-secretase activating protein (GSAP). Importantly, we found that the down-regulation of GSAP specifically reduces Aβ production in vivo. In order to characterize GSAP’s biological activity, we searched for GSAP-interacting proteins. I am currently looking for proteins that specifically control the activity of γ-secretase through GSAP modulation that could be used as novel therapeutic targets in order to circumvent the problems associated with non-selective γ secretase inhibition. These candidates are being validated through biochemical, molecular and behavioral experiments.

What results have you discovered thus far from your research, or what do you expect to find?

Dr. Karima Bettayeb: We identified the cellular partners of GSAP by several biochemical techniques. We identified interacting partners having potential relevance to the effect of GSAP on the production of Aβ peptide, based on their cellular functions. We performed functional validation of the candidates by measuring the effect of these proteins on Aβ production. Several of them have a dramatic effect on Aβ production. Several categories of proteins were found. We now propose to further validate and study these candidates and delineate the functional relationships that GSAP has with these interacting proteins using two major approaches: 1) addressing how these interactions affect APP processing in normal and pathological conditions, and 2) addressing how GSAP’s function is regulated by these candidates.

What impact might your work have on Alzheimer’s diagnosis or treatment in the future?

Dr. Karima Bettayeb: We believe that elucidating the impact of GSAP regulators on GSAP activity would help us understand how GSAP influences Aβ production and possibly delineate novel cellular pathways relevant to AD. Our goal is to identify new therapeutic targets that can specifically control the activity of γ-secretase through GSAP modulation, in order to circumvent the problems associated with non-selective γ-secretase inhibition.

What directions can you see your work taking in the future?

Dr. Karima Bettayeb: Working on the GSAP interacting proteins will hopefully help us determine GSAP-dependent cellular pathway(s) and also identify possible regulators of GSAP. Besides GSAP itself we believe that enzymatic regulators of GSAP could also represent novel potential therapeutic targets. Gleevec, the only compound known to affect GSAP, is not appropriate for Central Nervous System (CNS) applications because it doesn’t accumulate in the brain. In this context, any novel small molecule compound compatible with CNS application and targeting GSAP function or its regulators (e.g., modulate APP maturation without affecting other γ-secretase substrates) might be useful for developing specific treatments for AD. We will screen for or develop new inhibitors of GSAP and GSAP activators that have the capacity to concentrate in the brain. This work could lead to the discovery of drugs that will prevent the aggregation of Aβ and plaque formation and, thus, the deterioration and death of brain cells responsible for the devastating symptoms of Alzheimer’s disease.

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alzinfo - Dr. Marc Flajolet

Dr. Marc Flajolet: I am a molecular biologist by training, working on brain signaling in the context of aging and Alzheimer’s disease (AD) especially, for over 12 years now. In Dr. Greengard’s lab, we use an elaborate set of state-of-the-art techniques (ranging from molecular biology to behavioral studies) to discover novel biological functions relevant for AD. Our interest is to identify novel cellular targets or pathways important for AD and study how those can be used to design new drugs that would be beneficial for AD. I also work on identifying novel small molecule compounds that affect AD models and cultured cells in ways that show a potential to treat the disease.

If you had to sum up your work in a few sentences, what would you say?

Dr. Marc Flajolet: Dr. Greengard’s laboratory identified Gleevec, an FDA approved anti-cancer drug, as a novel potential drug to treat some aspects of AD. A few years later, we identified GSAP (gamma secretase activating protein) as the cellular target of Gleevec necessary for lowering beta amyloid. Currently we are characterizing the role and the biological function of GSAP in order to better design interfering molecules that could be used therapeutically to treat AD. One aspect of the work is to identify the proteins that interact with GSAP in order to further understand not only GSAP itself, but also the key regulators of GSAP—each of those could become novel therapeutic targets. Those putative novel targets are validated at various levels (e.g. in vitro, in vivo) and also in studies using large cohorts of AD patients, in collaboration with geneticists.

What results have you discovered thus far from your research, or what do you expect to find?

Dr. Marc Flajolet: Our group discovered that Gleevec could have potential as an anti-AD drug. We recently showed that Gleevec’s target GSAP, interacts with 7 proteins (unpublished), some of which are impacting positively and negatively on cellular models of AD. We expect to find strong links between at least some of the genes that code for the candidate proteins and AD in patients, and we are in the process of better delineating the cellular pathways involved in Gleevec function. We hope to develop small molecule compounds that will address therapeutic targets.

We have also discovered that Casein Kinase 1 (CK1) might represent an interesting target.  Inhibition of CK1 could lead to improvement in two major hallmarks of AD: reduction in beta amyloid production and reduction in Tau phosphorylation. We are currently working to establish the CK1 mechanism and we hope to bring to light the cellular target of CK1 that leads to these effects.

Along those lines we have recently shown that a small compound (SMER28) could be beneficial for AD via its role in autophagy activation. We hope to further develop this family of compounds and optimize their brain permeability in order to test their efficacy in vivo.

Dr. Marc Flajolet viewing cells through a microscope

What impact might your work have on Alzheimer’s diagnosis or treatment in the future?

Dr. Marc Flajolet: Our role most likely will impact the treatment much more that the diagnosis, but it is also possible that the genes we identify (such as the ones encoding proteins that interact with GSAP) could become important markers for the diagnosis of AD.

Any of the small molecule compounds that we identify has the capacity to become a drug to treat AD and therefore we put a lot of effort in this direction. We are working in a unique scientific environment that allows us to have access to a novel combination of techniques. This should help us tremendously to stay competitive and work at the highest possible pace.

What directions can you see your work taking in the future?

Dr. Marc Flajolet: We hope and believe that we will be able to move away from simple systems such as cellular tests and go forward toward more complex systems, and ideally bring some of our discoveries into pre-clinical studies and clinical trials.

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Dr. Paul Greengard – 2012 Annual Progress Report

“All attempts to develop a drug that stems the progression of Alzheimer’s disease or reverses its devastating mental decline have thus far failed large-scale clinical trials, in spite of the fact that most of these attempts have targeted beta amyloid, a toxic protein responsible for causing the major symptoms of Alzheimer’s. One of the main reason for these failures is that all of the drugs tested lack selectivity. Most have targeted beta amyloid and although some have succeed in lowering beta amyloid, they've run into trouble by targeting other processes that are vital to life.

"My laboratory has been making a coordinated effort to find ways in which drugs might selectively target beta amyloid without toxic side effects. Several projects in my lab are based on our recent discovery of Gamma Secretase Activating Protein (GSAP), which is responsible for stimulating the production of beta amyloid. We believe that GSAP will make an excellent target for drugs to treat the disease. That’s because drugs that utilize GSAP are expected to lower beta amyloid levels without inhibiting other processes necessary for health. Several of our promising Alzheimer’s projects are described in these personal interviews. It is my pleasure to introduce you to four Fisher Center for Alzheimer’s Disease Research scientists  Dr. Marc Flajolet, Dr. Karima Bettayeb, Dr. Jean-Pierre Roussarie, and Dr. Victor Bustos.”

Dr. Paul Greengard is the Vincent Astor Professor, Laboratory of Molecular and Cellular Neuroscience and Director of The Fisher Center for Alzheimer’s Research at The Rockefeller University. Dr. Greengard received his Ph.D. from Johns Hopkins University. Over the years, Dr. Greengard’s achievements have earned over 50 major achievement awards. In 2000, Dr. Greengard was awarded the Nobel Prize in Physiology or Medicine for his contributions to elucidating how neurotransmitters work in signal transduction in the nervous system. He is a member of the National Academy of Sciences and of the Institute of Medicine of the National Academies. He is an Honorary Member of the National Academies of Science in Sweden, Norway and Serbia and has been the recipient of many honorary degrees.

Dr. Greengard’s life work has been recognized around the world. He received the Karolinska Institutet’s Bicentennial Gold Medal on September 23, 2010 for his contributions to medical research and his leadership. This medal was the highest award conferred by Karolinska Institutet during its 200th anniversary celebrations. Since 1901, the Nobel Assembly at Karolinska Institutet has selected the Nobel laureates in Physiology or Medicine. “Dr. Greengard is one of the most prominent scientists of this century,” said Harriet Wallberg- Henriksson, President of Karolinska Institutet.

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Hacer ejercicio y perder peso resulta beneficioso para el cerebro

El ejercicio regular de alta intensidad no solo es bueno para el cuerpo, sino también para el cerebro, informan investigadores.

El nuevo estudio incluyó a adultos con sobrepeso e inactivos, con una edad promedio de 49 años, que se sometieron a pruebas para evaluar sus habilidades de pensamiento, toma de decisiones y memoria, lo que también se conoce como función cognitiva.

Los participantes del estudio comenzaron una rutina con una bicicleta de ejercicio y entrenamiento con pesas dos veces por semana. Tras cuatro meses, su peso, índice de masa corporal (una medida que se basa en la estatura y el peso), la masa grasa y la circunferencia de la cintura eran significativamente más bajos, y su capacidad de hacer ejercicio había aumentado un 15 por ciento en promedio.

Además, las pruebas de seguimiento mostraron que la función cerebral de los participantes también había mejorado, y que los aumentos eran proporcionales a las mejoras en la capacidad de ejercicio y en el peso corporal. Dicho de otra forma, mientras más ejercicio podían hacer y más peso habían perdido, mayor era la mejora en las habilidades de pensamiento, hallaron los investigadores.

El estudio será presentado el lunes en el Congreso Cardiovascular Canadiense en Toronto.

"Si uno habla con las personas que hacen ejercicio, afirman que se sienten más agudas. Ahora, hallamos una forma de medirlo", señaló en un comunicado de prensa de la Heart and Stroke Foundation of Canada el Dr. Martin Juneau, director de prevención del Instituto Cardiológico de Montreal.

Durante el ejercicio, el flujo sanguíneo al cerebro aumenta. Mientras mejor sea la condición física, más aumenta el flujo sanguíneo, explicó Juneau.

Un declive en la función cerebral es una parte normal del envejecimiento, pero el declive puede ser peor entre las personas que sufren de enfermedades cardiacas, apuntó.

"Es tranquilizador saber que uno puede prevenir al menos parcialmente ese declive mediante el ejercicio y la pérdida de peso", planteó Juneau en el comunicado de prensa.

Aunque el estudio encontró una relación entre una mejor condición física y mejoras en las habilidades de pensamiento, no demostró que existiera causalidad.

Los datos y las conclusiones de las investigaciones presentadas en reuniones médicas se deben considerar como preliminares hasta que se publiquen en una revista revisada por profesionales.

FUENTE: Heart and Stroke Foundation of Canada, news release, Oct. 29, 2012

gSAP: A Key Protein in Plaque Formation

Dr. Gen He and Dr. Paul Greengard of the Fisher Center for Alzheimer’s Disease Research laboratory have discovered a protein that stimulates the production of beta-amyloid, the toxic protein that is linked to the development of plaques in the brain that are typically associated with Alzheimer’s disease. This important discovery has the potential to guide the development of highly effective and safe drugs that could treat the underlying cause of Alzheimer’s, and thus stop or slow the disease’s progression.

Their findings were published in the September 2, 2010 edition of the journal Nature.

Dr. He and Dr. Greengard have identified gamma secretase activating protein (gSAP), and showed that it stimulates an enzyme called gamma secretase that is responsible for producing beta-amyloid. The researchers also discovered that the anti-cancer drug, Gleevec, binds to gSAP, preventing it from activating gamma secretase. Fisher Center researchers had previously discovered that Gleevec lowers levels of beta-amyloid in the brain by blocking the activity of gamma secretase, but they did not know how Gleevec did this or whether it was affecting gamma secretase directly or indirectly, through another protein. “I was researching the mechanism of Gleevec’s effect of lowering amyloid,” says Dr. He. “My preliminary results indicated that Gleevec works by indirectly inhibiting gamma secretase. Therefore, I started to search for a specific protein that is targeted by Gleevec and regulates gamma secretase activity. This is how gSAP was found.”

Dr. Paul Greengard

Just as importantly, the process of inhibiting gSAP did not prove toxic to nerve cells or other body cells, a factor that has plagued many other experimental treatments that inhibit beta-amyloid. This discovery therefore opens a new door for research into highly specific anti-amyloid drugs that do not harm the body. That’s what Dr. He and his team are engaged in now. “We are working on selecting more potent drug-like compounds that selectively target gSAP and reduce plaques in experimental animal models; hopefully this will provide new treatments for Alzheimer’s,” Dr. He says.

“Millions of people suffer from Alzheimer’s disease, and treatment options are limited,” says Dr. Paul Greengard, Nobel Laureate and director of the Fisher Center for Alzheimer’s Disease Research laboratory at The Rockefeller University. “Existing drugs may mask symptoms for a time but do nothing to stop the relentless downward progression of Alzheimer’s. What is needed are safe and effective medications that will halt the cause of the underlying disease. It is our hope that this gamma secretase activating protein will greatly add to the creation of safe and effective Alzheimer’s treatments.”

Kent Karosen, President and CEO of the Fisher Center for Alzheimer’s Research Foundation says, “We are so proud of the scientists we support, and would like to
specifically congratulate Drs. He and Greengard for discovering this important protein. Their latest research is a potential paradigm shift in how scientists and doctors around the world will attack Alzheimer’s.”

For more information, visit Dr. Greengard's profile.

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El aprendizaje acelerado de un nuevo idioma podría ayudar al cerebro a crecer

Unos escáneres antes y después de un programa de trece meses hallaron cambios en los adultos con fluidez recién adquirida

Aprender un nuevo idioma en un periodo corto parece hacer que el cerebro crezca, sugiere una investigación reciente.

El nuevo estudio incluyó a reclutas jóvenes de la Academia de Interpretación de las Fuerzas Armadas Suecas, que pasaron de no tener ningún conocimiento de un nuevo idioma a hablarlo con fluidez en un plazo de trece meses. Los reclutas estudiaron a un ritmo furioso: desde la mañana hasta la tarde, los días de semana y los fines de semana.

Los reclutas fueron comparados con estudiantes de medicina y ciencias cognitivas de una universidad (el grupo de control), que también estudiaban mucho, pero que no aprendían un nuevo idioma.

Ambos grupos se sometieron a IRM cerebrales antes y después de un periodo de estudio intensivo de tres meses de duración. Los escáneres mostraron que la estructura cerebral del grupo de control permaneció sin cambios, pero ciertas partes de los cerebros de los estudiantes de idiomas crecieron.

Este crecimiento se observó en el hipocampo, una estructura que tiene que ver con el aprendizaje de material nuevo y con la navegación espacial, y en tres áreas de la corteza cerebral.

Entre los reclutas, los que tuvieron un rendimiento naturalmente alto en el aprendizaje del nuevo idioma mostraron un mayor crecimiento en el hipocampo y en las áreas de la corteza cerebral relacionadas con el aprendizaje de idiomas, mientras que los que tuvieron que esforzarse más por aprender un nuevo idioma tuvieron un mayor crecimiento en un área de la región motora de la corteza cerebral, hallaron los investigadores.

"Nos sorprendió que distintas partes del cerebro se desarrollaron a distintos grados, dependiendo de qué tanto rendían los estudiantes y cuánto esfuerzo tenían que dedicar para mantenerse al día en el curso", señaló en un comunicado de prensa de la Universidad de Lund Johan Martensson, investigador en psicología de la universidad, en Suecia.

Martensson anotó que investigaciones anteriores han indicado que las personas bilingües y multilingües desarrollan la enfermedad de Alzheimer a una edad más tardía.

"Aunque no podemos comparar tres meses de estudio intensivo de un idioma con toda una vida de bilingüismo, muchas cosas sugieren que aprender idiomas es una buena forma de mantener el cerebro en forma", apuntó Martensson.

El estudio aparece en la edición del 15 de octubre de la revista NeuroImage

FUENTE: Lund University, news release, October 2012