ScienceDaily (July 16, 2010) — Investigators have found that fruit fly (Drosophila melanogaster) males -- in which the activity of an Alzheimer's disease protein is reduced by 50 percent -- show impairments in learning and memory as they age. What's more, the researchers were able to prevent the age-related deficits by treating the flies with drugs such as lithium, or by genetic manipulations that reduced nerve-cell signaling.
In the example shown in still image from a video, a female fruit fly is receptive to his courtship, keeping him interested and ending with mating. If the female had not been receptive she would release less attractive pheromones and would have more aggressively discouraged the male to court her. Under these conditions, the male will quickly learn to not court females and will remember this for several hours. This ability to train males to learn and remember with courtship behavior was used to test for learning and memory defects in a fly model for familial Alzheimer's disease. (Credit: Thomas A. Jongens, PhD, University of Pennsylvania School of Medicine)
Their findings are published in theJournal of Neuroscience.
"The results from our study suggest a new route to explore for the treatment of familial Alzheimer's disease and possibly the more common sporadic forms of Alzheimer's disease," notes Jongens. "They also reveal that proper presenilin activity levels are required to maintain normal cognitive capabilities during aging."
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Neurobiology of Disease
Journal of Neuroscience, 2010; 30: 9510-9522
Journal of Neuroscience, 2010; 30: 9510-9522
Pharmacological and Genetic Reversal of Age-Dependent Cognitive Deficits Attributable to Decreased presenilin Function
Sean M. J. McBride,1,2 * Catherine H. Choi,1,2,3 * Brian P. Schoenfeld,1,2 * Aaron J. Bell,1,2 David A. Liebelt,1,2 David Ferreiro,1,2Richard J. Choi,1,2 Paul Hinchey,1,2 Maria Kollaros,1,2 Allison M. Terlizzi,1,2 Neal J. Ferrick,1,2 Eric Koenigsberg,1,2 Rebecca L. Rudominer,1,2Ai Sumida,4 Stephanie Chiorean,4 Kathleen K. Siwicki,5 Hanh T. Nguyen,1,2 Mark E. Fortini,6 Thomas V. McDonald,1,2 and Thomas A. Jongens4
1Section of Molecular Cardiology and 2Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461,3Department of Dermatology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, 4Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, 5Department of Biology, Swarthmore College, Swarthmore, Pennsylvania 19081, and 6Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
Correspondence should be addressed to any of the following: Sean M. J. McBride, c/o Thomas McDonald Lab, Section of Molecular Cardiology and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer G35, 1300 Morris Park Avenue, Bronx, NY 10461, Email: smcbride@aecom.yu.edu; Thomas McDonald, Section of Molecular Cardiology and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer G35, 1300 Morris Park Avenue, Bronx, NY 10461, E-mail: Email: mcdonald@aecom.yu.edu; or Thomas A. Jongens, Department of Genetics, University of Pennsylvania, School of Medicine, 538A CRB, 415 Curie Boulevard, Philadelphia, PA 19104, E-mail: Email: jongens@mail.med.upenn.edu
Abstract
Alzheimer's disease (AD) is the leading cause of cognitive loss and neurodegeneration in the developed world. Although its genetic and environmental causes are not generally known, familial forms of the disease (FAD) are attributable to mutations in a single copy of the Presenilin (PS) and amyloid precursor protein genes. The dominant inheritance pattern of FAD indicates that it may be attributable to gain or change of function mutations. Studies of FAD-linked forms of presenilin (psn) in model organisms, however, indicate that they are loss of function, leading to the possibility that a reduction in PS activity might contribute to FAD and that proper psn levels are important for maintaining normal cognition throughout life. To explore this issue further, we have tested the effect of reducing psn activity during aging in Drosophila melanogaster males. We have found that flies in which the dosage of psn function is reduced by 50% display age-onset impairments in learning and memory. Treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium during the aging process prevented the onset of these deficits, and treatment of aged flies reversed the age-dependent deficits. Genetic reduction of Drosophila metabotropic glutamate receptor (DmGluRA), the inositol trisphosphate receptor (InsP3R), or inositol polyphosphate 1-phosphatase also prevented these age-onset cognitive deficits. These findings suggest that reduced psn activity may contribute to the age-onset cognitive loss observed with FAD. They also indicate that enhanced mGluR signaling and calcium release regulated by InsP3R as underlying causes of the age-dependent cognitive phenotypes observed when psn activity is reduced.
Received Feb. 25, 2010; revised March 31, 2010; accepted June 1, 2010.
Correspondence should be addressed to any of the following: Sean M. J. McBride, c/o Thomas McDonald Lab, Section of Molecular Cardiology and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer G35, 1300 Morris Park Avenue, Bronx, NY 10461, Email: smcbride@aecom.yu.edu; Thomas McDonald, Section of Molecular Cardiology and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer G35, 1300 Morris Park Avenue, Bronx, NY 10461, E-mail: Email: mcdonald@aecom.yu.edu; or Thomas A. Jongens, Department of Genetics, University of Pennsylvania, School of Medicine, 538A CRB, 415 Curie Boulevard, Philadelphia, PA 19104, E-mail: Email: jongens@mail.med.upenn.edu
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