Tuesday, September 26, 2006

The Brain that Squeaked

From today's New York TImes:

Atlas Squeaked: A Complete Map of the Brain of a Mouse
By NICHOLAS WADE
Published: September 26, 2006
The New York Times

Scientists have gained a new window for peering into the brain, courtesy of a $41 million project financed by Paul G. Allen, the co-founder of Microsoft.

The project is an electronic atlas that shows which genes are switched on in neurons throughout the brain of a mouse.

Instead of looking at one gene at a time in one or a few neurons, researchers can now study all the brain genes systematically. And instead of having to visualize each gene experimentally, everything is available online. “I am using it all the time,” said Catherine Dulac, who studies mouse behavior at Harvard. “It’s an extraordinary resource.”

Marc Tessier-Lavigne, an expert on neuronal signaling and vice president for research at Genentech, said he would put the new brain atlas “on a par with the human genome project.” Both are members of the scientific advisory board overseeing the project.

Thomas M. Jessel, a neuroscientist at Columbia University, said after looking at the atlas that it was of high quality and would complement other available brain maps.

“It is likely to be the standard source for the next few years” for people interested in the pattern of gene activation in the brain,” Professor Jessel said.

[ ... Read the full article ... ]

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Anthony H. Risser | |

Abstract of the Day: Alzheimer Disease Drug Treatments

Brinton RD & Wang JM (2006). Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res., 3(3), 185-190.

Department of Molecular Pharmacology and Toxicology and Program in Neuroscience, Pharmaceutical Science Center, 1985 Zonal Avenue, University of Southern California, Los Angeles, CA 90033, USA.

A major challenge not yet addressed by current therapeutic interventions for Alzheimer's disease (AD) is the regeneration of lost neurons and neural circuitry to restore cognitive function. Therapies that lead to cessation of the degenerative process still leave the brain riddled with deteriorated neural circuits and reduced neuron number. The discovery of neurogenesis in the adult brain and the regenerative potential of neural stem cells holds the promise for restoration of neural populations and regeneration of neural circuits necessary for cerebral function. While the regenerative potential of neural stem cells is great, so too is the challenge of delivering neural stem cells to the brain. Basic science analyses and human trials indicate that constituents of microenvironments within the brain determine the neurogenic potential, phenotypic differentiation of neural stem cells and magnitude of the neural stem cell pool. Multiple analyses have documented that dentate neurogenesis is regulated by multiple growth factors which are abundant during development and which dramatically decline with age. While the cause(s) of age-associated decline in neurogenesis remains to be fully determined, loss in growth factors, FGF-2, IGF-1 and VEGF, in the microenvironment of the subgranular zone (SGZ) are prime contributors to the reduced neurogenic potential. The decline in dentate neurogenesis can be observed as early as middle age. In the aged and AD brain, both the pool of neural stem cells and their proliferative potential are markedly diminished. In parallel, the level of potential regenerative factors is diminished in the brains of Alzheimer's patients compared to age-matched controls. Our efforts have been directed towards discovery and development of small, blood brain barrier penetrant molecules to promote endogenous proliferation of neural stem cells within the brain. These endeavors have led to the discovery that the neurosteroid alloprognanolone (APalpha) is a potent and highly efficacious proliferative agent in vitro and in vivo of both rodent and human neural stem cells. Results of our in vitro studies coupled with our more recent analyses in the triple transgenic mouse model of AD suggest that APalpha is a promising strategy for promoting neurogenesis in the aged brain and potentially for restoration of neuronal populations in brains recovering from neurodegenerative disease or injury. A brief overview of issues impacting the therapeutic potential of neurogenesis and the factors used to promote neurogenesis in the aging and degenerating brain is presented. Also included is a review of our current research into the neurogenic potential of the small molecule, blood brain barrier penetrating, neurosteroid allopregnanolone (APalpha).

PMID: 16842093 [PubMed - indexed for MEDLINE]

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Anthony H. Risser | |

Sunday, September 17, 2006

Beck Gets a Lasker

From today's Philadelphia Inquirer:

Penn psychiatrist to be honored today
Aaron T. Beck will receive the prestigious Lasker Award for his pioneering work in cognitive therapy.
By Josh Goldstein
Inquirer Staff Writer
17 September 2006

In the 1960s, University of Pennsylvania psychiatrist Aaron T. Beck began to develop the theories and practice of a new branch of psychoanalysis known as cognitive therapy.

Beck's more than 40 years of pioneering work at Penn is being honored today with the prestigious Albert Lasker Award for Clinical Medical Research.

The Lasker awards are given annually for "stunning" achievements in basic and clinical research in medicine. The awards are often likened to Nobel Prizes and come with a $100,000 honorarium.

Cognitive therapy, which treats mental problems including depression, anxiety disorders and phobias, is based on the premise that thoughts, feelings and actions are interwoven. Patients are taught to identify their negative, sometimes irrational patterns of thought and replace them with more realistic, helpful ones.

Beck's development of cognitive therapy "is one of the most important advances - if not the most important advance - in the treatment" of depression and other anxiety disorders in the last 50 years, said Joseph L. Goldstein, a 1985 Nobel laureate for medicine and chairman of the jury of researchers who selected the latest Lasker winners.

"This was really quite an unexpected, but very much appreciated, honor," Beck said.

[ ... Read the full article ... ]

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Anthony H. Risser | |

Friday, September 08, 2006

Abstract of the Day: Alzheimer Disease

Pavlik VN, Doody RS, Massman PJ, & Chan W. (2006). Influence of premorbid IQ and education on progression of Alzheimer's Disease. Dementia, Geriatrics, & Cognitive Disorders,22(4), 367-377. [Epub ahead of print]

Department of Family and Community Medicine, Baylor College of Medicine, Houston, Tex., USA.

Background: Lower education is associated with a higher risk of developing Alzheimer's disease (AD). Years of education and measures of general intellectual function (IQ) are highly correlated. It is important to determine whether there is a relationship between education and AD outcomes that is independent of IQ. Objective: To test the hypothesis that premorbid IQ is a stronger predictor of cognitive decline, global progression, and overall survival, than education in patients with AD. Methods: The study included 478 probable AD patients (322 women and 156 men, mean age 74.5 years) followed in a large AD referral center for a mean of 3.2 years. Eligible participants had a baseline estimate of premorbid IQ using the American version of the Nelson Adult Reading Test (AMNART) and at least one follow-up visit with complete neuropsychological assessment. We used random effects linear regression analysis, and Cox proportional hazards analysis to determine whether or not education and/or premorbid IQ were independently associated with cognitive decline, global progression of AD, and survival. Results: When the baseline AMNART score was included in regression models along with education and other demographic variables, AMNART score, but not education, was associated with a higher baseline score and slower rate of decline in MMSE and ADAS-Cog scores, and the Clinical Dementia Rating sum of boxes score. Neither higher premorbid IQ nor higher education was associated with longer survival. Conclusions: We conclude that a baseline AMNART score is a better predictor of cognitive change in AD than education, but neither variable is associated with survival after diagnosis. Copyright (c) 2006 S. Karger AG, Basel.

PMID: 16954693 [PubMed - as supplied by publisher]

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Anthony H. Risser | |

Thursday, September 07, 2006

Knockout Mice are the Bomb!

From an NIH press release from earlier today:

NIH Launches Knockout Mouse Project
Genome-Wide Public Resource Will Provide New Mouse Models for Understanding Human Disease


The National Institutes of Health (NIH) today awarded a set of cooperative agreements, totaling up to $52 million over five years, to launch the Knockout Mouse Project. The goal of this program is to build a comprehensive and publicly available resource of knockout mutations in the mouse genome. The knockout mice produced from this resource will be extremely useful for the study of human disease.

The NIH Knockout Mouse Project will work closely with other large-scale efforts to produce knockouts that are underway in Canada, called the North American Conditional Mouse Mutagenesis Project (NorCOMM), and in Europe, called the European Conditional Mouse Mutagenesis Program (EUCOMM). The objective of all these programs is to create a mutation in each of the approximately 20,000 protein-coding genes in the mouse genome.

“Knockout mice are powerful tools for exploring the function of genes and creating animal models of human disease. By enabling more researchers to study these knockouts, this trans-NIH initiative will accelerate our efforts to translate basic research findings into new strategies for improving human health,” said NIH Director Elias A. Zerhouni, M.D. “It is exciting that so many components of NIH have joined together to support this project, and that the NIH Knockout Mouse Project will be working hand-in-hand with other international efforts. This is scientific teamwork at its best.”

Knockout mice are lines of mice in which specific genes have been completely disrupted, or “knocked out.” Systematic disruption of each of the 20,000 genes in the mouse genome will allow researchers to determine the role of each gene in normal physiology and development. Even more importantly, researchers will use knockout mice to develop better models of inherited human diseases such as cancer, heart disease, neurological disorders, diabetes and obesity. Recent advances in recombinant DNA technologies, as well as completion of the mouse genome sequence, now make this project feasible.

NIH today awarded five-year cooperative agreements totaling up to $47.2 million to two groups for the creation of the knockout mice lines. Recipients of those awards are Regeneron Pharmaceuticals, Inc., in Tarrytown, N.Y., and a collaborative team from Children’s Hospital Oakland Research Institute (CHORI) in Oakland, Calif.; the School of Veterinary Medicine, University of California, Davis (UC Davis); and the Wellcome Trust Sanger Institute in Hinxton, England.

In addition, NIH awarded another five-year cooperative agreement totaling $2.5 million to the Jackson Laboratory in Bar Harbor, Maine for the establishment of a NIH Knockout Mouse Project data coordination center. Finally, NIH awarded cooperative agreements to the University of Pennsylvania in Philadelphia and to the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto to improve the efficiency of methods for creating knockout lines. Those agreements total about $2.5 million and run for three and two years, respectively.

[ ... Read the full release ... ]

NIH Knockout Mouse Project website
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Anthony H. Risser | |

Wednesday, September 06, 2006

p16-Ink4a

From The New York Times:
Gene Found to Switch Off Stem Cells During Aging
By NICHOLAS WADE

Published: September 6, 2006

Biologists have uncovered a deep link between lifespan and cancer in the form of a gene that switches off stem cells as a person ages.

The critical gene, already well known for its role in suppressing tumors, seems to mediate a profound balance between life and death. It weighs the generation of new replacement cells, required for continued life, against the risk of death from cancer, which is the inevitable outcome of letting cells divide. To offset the increasing risk of cancer as a person ages, the gene gradually reduces the ability of stem cells to proliferate.

The new finding, reported by three groups of researchers online Wednesday in Nature, was made in a special breed of mice that lack the pivotal gene, but is thought likely to apply to people as well.

The finding indicates that many of the degenerative diseases of aging are caused by an active shutting down of the stem cells that renew the body’s various tissues, and are not just a passive disintegration of tissues under life’s daily wear and tear, as is often assumed.

[ ... Read the full article ... ]

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Anthony H. Risser | |