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Topic Name: Researchers find children with gene show reduced cognitive function

Category: Biomedical

Research persons: Jacob Raber, Ph.D., Summer Acevedo, Ph.D., Byung Park, Ph.D.

Location: Oregon Health & Science University, United States

Details

Children who possess a gene known to increase the risk of Alzheimer's disease already show signs of reduced cognitive function, an Oregon Health & Science University study has found.

Scientists in the OHSU School of Medicine discovered that 7- to 10-year-olds with a member of a family of genes implicated in development, nerve cell regeneration and neuroprotection display reduced spatial learning and memory, associated with later-life cognitive impairments.

Results of the study, presented today at Neuroscience 2007, the 37th annual meeting of the Society for Neuroscience in San Diego, suggest that changes predisposing a person to Alzheimer's and other forms of dementia might occur much sooner in the brain than previously thought.

"One of our questions has been is this a risk that only happens with age, or is it already - early on - the cause of differences in performance," said study co-author Jacob Raber, Ph.D., associate professor of behavioral neuroscience and neurology in the OHSU School of Medicine. "This study suggests there already are cognitive differences very early on in life."

The results also mean therapeutic interventions that delay the effects of cognitive decline may be possible at a much younger age, Raber says.

Previous studies have shown that a member of the apolipoprotein E gene family, apoE4, increases a person's risk of age-related cognitive decline and cognitive injury from such "environmental" challenges as brain trauma. Mice expressing human apoE4 developed progressive, age-dependent impairments in spatial learning and memory.

Half of all people with Alzheimer's disease carry apoE4, Raber said.

"When we looked at non-demented healthy elderly, we saw the clear effect of apoE4," he said. "So it's not just Alzheimer's disease. ApoE4 carriers generally do worse in our tests. Among the nondemented oldest old, where the mean age is 82, those who have apoE4 do less well" on cognitive tests.

In their study on children, Raber and colleagues - lead author Summer Acevedo, Ph.D., OHSU postdoctoral fellow, and Byung Park, Ph.D., senior biostatistics associate in the OHSU Biostatistics & Bioinformatics Shared Resource - examined 55 healthy boys and girls ages 7 to 10. Among them were eight girls and six boys who carried the apoE4 gene, and 17 girls and 24 boys who didn't.

The children were assessed using a combination of paper- and computer-based tests, including a 3-dimensional, virtual reality program called "Memory Island" that assesses spatial learning and memory. "Memory Island" immerses participants in a simulated world in which they must navigate to a location marked with a flag that's adjacent to the target in each of four quadrants. The participants are given several tries to navigate back to the targets based on memory.

The computer program mimics the Morris water maze, a standard scientific tool for testing memory in rodents by training them to swim to a platform based on visual cues.

Raber, Acevedo and Park found that apoE4 carriers scored lower in location recognition tests, and non-apoE4 carriers outperformed apoE4 carriers in the "Memory Island" test by navigating closer to the visible target location. Also, non-apoE4 carriers showed spatial memory retention when a target wasn't present and searched more frequently for the targets in the appropriate quadrants while apoE4 carriers did not.

In all, 75.6 percent non-apoE4 carriers showed target preference compared with only 43 percent of apoE4 carriers.

The study was supported by the Ellison Medical Foundation, the Clinical Research Enhancement Fund and the Public Health Service.

Note for Alzheimer's disease

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease that, in its most common form, is found in people over age 65. Approximately 24 million people worldwide have dementia of which the majority (~60%) is due to Alzheimer's.
Clinical signs of Alzheimer's disease are characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes. It is the most common type of dementia. Plaques which contain misfolded peptides called amyloid beta (Aβ) are formed in the brain many years before the clinical signs of Alzheimer's are observed. Together, these plaques and neurofibrillary tangles form the pathological hallmarks of the disease. These features can only be discovered at autopsy and help to confirm the clinical diagnosis. Medications can help reduce the symptoms of the disease, but they cannot change the course of the underlying pathology.

Note for Apolipoprotein E

Apolipoprotein E (APOE), a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells.
Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. Apolipoprotein E, a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells. ApoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. The APOE gene is mapped to chromosome 19 in a cluster with APOC1 and APOC2. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants.

Note for  Neuroprotection

The term neuroprotection refers to mechanisms within the nervous system which protect neurons from apoptosis or degeneration, for example following a brain injury or as a result of chronic neurodegenerative diseases. The word derives from the words "neuron" (Greek for nerve cell) and "protection" (Latin for "saving").
Currently, there is a broad interest in how apoptosis and neuroprotection act on the brain in situations as different as growing up and learning or being ill (stroke, schizophrenia, Parkinson's disease).
A recent post-mortem study of the anterior cingulate cortex of persons with schizophrenia found increased levels of cellular signaling proteins, primarily PEBP, that may lead to increased levels of neuroprotection.

About Researchers

Jacob Raber
Associate Professor, Behavioral Neuroscience, OHSU
Associate Professor, Department of Neurology, OHSU
Affiliate Associate Scientist, Division of Neuroscience, ONPRC, OHSU
e-mail: raberj@ohsu.edu

Education
B.Sc. (1983) Free University, Amsterdam, The Netherlands
M.Sc. (1986) Free University, Amsterdam, The Netherlands
Ph.D. (1991) The Weizmann Institute of Science, Rehovot, Israel

Research Interests
Our research focuses on the effects of genetic and environmental factors on brain structure and function in experimental mouse models of human neurological diseases. Based on what we learn in the mouse models, we try to develop tests and treatment strategies to improve brain function in humans suffering from these diseases. Routinely, we use a combination of behavioral, neuroendocrinological, pharmacological, neurochemical, immunohistochemical, cellular, and molecular approaches.

Jin Byung Park, Ph.D.
Post-Doctorate Researcher
University of California, Berkeley

Ph.D. Biocatalysis and Biotransformation, 2004
Swiss Federal Institute of Technology (ETH), Zurich
M.S. Biochemical Engineering, 1995
Seoul National University, Korea
B.S. Food Science and Technology, 1993
Seoul National University, Korea
jbpark@berkeley.edu
Office Location: 497A Tan Hall
Office Telephone: 643-8340
Office Fax: 643-1228 

About Funds

United States Public Health Service

The United States Public Health Service is comprised of all Agency Divisions of Health and Human Services and the Commissioned Corps. The Assistant Secretary for Health (ASH) oversees the PHS and the United States Public Health Service Commissioned Corps.
The mission of the U.S. Public Health Service Commissioned Corps is to protect, promote, and advance the health and safety of the United States. As the USA's uniformed service of public health professionals, the Commissioned Corps achieves its mission through:

Rapid and effective response to public health needs 
Leadership and excellence in public health practices 
Advancement of public health science

Ellison Medical Foundation

The Ellison Medical Foundation supports basic biomedical research on aging relevant to understanding lifespan development processes and age-related diseases and disabilities. 

The Foundation particularly wishes to stimulate new, creative, research that might not be funded by traditional sources or that is often under-funded in the U.S. 

The Ellison Medical Foundation fosters research by means of grants-in-aid on behalf of investigators to universities and laboratories within the United States. Institutions receiving awards must be tax-exempt 501(c)(3) organizations or U.S. colleges or universities. Eligible U.S. institutions may enter into consortium or subcontractual agreements with other non-profit organizations, either in the U.S. or elsewhere, as necessary to the scientific goals of the project.

Oregon Health & Science University

Oregon Health & Science University (OHSU) is a public university in Oregon with a main campus, including three hospitals, in Portland and a smaller campus in Hillsboro. It was formed in 1974 as the University of Oregon Health Sciences Center, combining state dentistry, medicine, and nursing programs into a single center. It was renamed Oregon Health Sciences University in 1981 and took its current name in 2001, as part of a merger with the Oregon Graduate Institute of Science and Technology (OGI) in Hillsboro. In addition, the university has several partnership programs including a joint PharmD Pharmacy program with Oregon State University.