Two papers in the July 6, 2006, Neuron, published by Cell Press, report evidence that surprisingly simple genetic abnormalities in the machinery of critical neuronal growth-regulating molecules can kill neurons in Down's syndrome, Alzheimer's disease, and other neurodegenerative disorders. The researchers said their basic findings could aid progress toward treatment for the cognitive deficits in these disorders.
The growth-regulating "neurotrophins" whose functional failure they studied are taken up by neurons in sac-like carriers called "endosomes" and transported to the main cell body, where they exert their influence. Neurotrophins regulate neuronal development and connectivity by activating protein switches called Trk receptors in neurons.
The two papers were led by William C. Mobley and Ahmad Salehi of Stanford University (Salehi et al.) and Susan G. Dorsey at the University of Maryland Baltimore School of Nursing and Lino Tessarollo of the National Cancer Institute (Dorsey et al.).
In humans, Down's syndrome is caused by a trisomy--an abnormal three copies of chromosome 21. Such trisomy causes an increased "dosage" of genes on that chromosome, and a central mystery of Down's syndrome is how such an overdose of particular genes leads to such abnormalities as mental retardation.
In their papers, Salehi and colleagues and Tessarollo and colleagues studied mice genetically engineered to mimic the trisomy seen in human Down's syndrome. Their aim was to discover the machinery by which this trisomy ultimately causes the death of neurons that are important for cognitive function.
Salehi et al. find that an increase in the expression of only one gene, for amyloid precursor protein (APP), disrupts transport of the neurotrophin "nerve growth factor" (NGF). APP is also a central molecule in the pathology of Alzheimer's disease.
The Dorsey et al. paper describes how restoring the normal cellular levels of a Trk receptor for the neurotrophin "brain-derived neurotrophin factor" (BDNF) rescues neuronal death in another mouse model of Down's syndrome.
Salehi et al. found that the NGF transport disruption leads to the degeneration of "basal forebrain cholinergic neurons" (BFCNs) important for cognitive function. This deterioration of BFCNs is similar to that seen in Alzheimer's disease and is caused by abnormal APP function. Since in people with Down's syndrome, the APP gene resides on the trisomic chromosome, Salehi and colleagues reasoned that an overdose of APP might also play a role in neuronal degeneration in Down's syndrome and thereby contribute to cognitive deficits in both Down's syndrome and Alzheimer's disease.
Thus, in their studies, the researchers tested the effects of APP dosage by using three trisomic mouse strains. One strain was trisomic on the chromosome that largely corresponds to the one involved in human Down's syndrome. A second mouse strain was trisomic for many of the genes, but not for APP. And a third mouse strain was the same as the first, except that the third copy of the APP gene was deleted.
In their experiments, Salehi and colleagues found decreased NGF transport within the forebrain neurons in the fully trisomic mouse, but not the ones lacking APP trisomy. And, in studies of mice with different doses of the APP gene, they found that the greater the APP dose, the worse the NGF transport. What's more, the researchers' analysis of NGF-carrying endosomes in the affected neurons yielded evidence that the APP protein overloaded those endosomes, decreasing NGF transport.
Salehi and colleagues concluded that "In pointing to the importance of gene dose and overexpression of a specific gene in the setting of trisomy, the current study is expected to enhance progress in understanding the cellular mechanism of pathogenesis for neurodegeneration in DS. It makes the argument that even in the context of a complex genetic lesion, increased dose for but one gene can impact important features of neuronal structure and function. Though other genes in the trisomic segment must contribute to the defect in NGF transport and to degenerative changes, our report draws attention to a surprisingly robust effect of the dose for App."
The researchers also wrote that "increased gene dose for APP may contribute significantly to the pathogenesis of AD-related changes and dementia in people with DS, including the degeneration of BFCNs. If so, treatments to reduce APP gene expression may prove valuable."
The paper by Tessarollo and colleagues explored the mechanism of neuronal cell death in another trisomic mouse model. In previous studies, they had found that trisomy causes an overproduction of a truncated version, or "isoform," of a Trk neurotrophin receptor. This overproduction compromises BDNF function and causes the death of neurons in the hippocampus, they found. The hippocampus is a major center in the brain for learning and memory. The researchers also found in their previous work that they could restore survival of these neurons by overexpressing the full-length Trk receptor.
In the new Neuron paper, Tessarollo and colleagues found that they could also prevent neuronal cell death by genetic manipulation to reduce the truncated Trk receptor to normal levels.
The researchers concluded that "Our results suggest that alterations of receptor isoform expression can affect neurotrophin signaling and consequently neuron survival." "Small alterations in neurotrophin/Trk receptor activation like those seen in [the trisomic mouse model] may be directly linked to neurodegenerative diseases."
Tessarollo and colleagues also noted that "Alterations in neurotrophins or their Trk receptor levels have been reported in a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's, Huntington's, and Parkinson's diseases. However, it is still unclear whether changes in expression of these receptors are involved in the pathogenic process or are an indirect effect of the disease."
A lack of good animal models had prevented scientists from exploring the effects of Trk receptor abnormalities on neuronal cell death, wrote Tessarollo and colleagues. However, they wrote, their trisomic mouse strain has enabled such studies, with surprising results.
"The cause of the accelerated cell death has the potential to be multigenic, since hundreds of genes are dysregulated in trisomies," they wrote. "Surprisingly, we have found that an alteration in TrkB receptor signaling is sufficient for the development of this phenotype, suggesting that dysregulation of a single gene is sufficient to cause cellular alterations resulting in neuron death."
In a preview of the two papers, Eero Castrén and Heikki Tanila of the University of Helsinki wrote in the same issue of Neuron "Although the results of these studies are still far from suggesting any new therapeutic strategies for Down's syndrome, it might be possible that drugs influencing APP processing could in the future help to restore the retrograde transport of NGF and thereby cognitive symptoms in Down's syndrome. In any case, the papers provide interesting insights into the pathophysiology of Down's syndrome and underline the notion that the primary aim of treatment of neurodegenerative disorders is not to keep neurons alive but to keep them connected."
(Salehi et al.)
The researchers include Ahmad Salehi, Pavel V. Belichenko, Ke Zhan, Chengbiao Wu, Janice S. Valletta, Ryoko Takimoto-Kimura, Alexander M. Kleschevnikov and William C. Mobley of Stanford University in Stanford, CA; Jean-Dominique Delcroix of Stanford University in Stanford, CA and the European Brain Research Institute, Rita Levi-Montalcini Foundation in Rome, Italy; Kumar Sambamurti and Peter P. Chung of the Medical University of South Carolina in Charleston, SC; Weiming Xia and William A. Campbell of Harvard Medical School in Boston, MA; Angela Villar, Charles J. Epstein, of University of California, San Francisco in San Francisco, CA; Laura Shapiro Kulnane and Bruce T. Lamb of Case Western Reserve University in Cleveland, OH; Ralph A. Nixon of Nathan Kline Institute in Orangeburg, NY; Gorazd B. Stokin and Lawrence S.B. Goldstein of University of California, San Diego in La Jolla, CA; of Stanford University and Stanford University School of Medicine in Stanford, CA.
This research was sponsored by grants from the NIA (AG16999, W.C.M.), NINDS (NS38869, W.C.M.), NICHD (31498, C.J.E.), Adler Foundation (J.D.D.), Alzheimer Association and State of California Alzheimer's Program (A.S. and W.C.M.), McGowan Charitable Trust, Larry L. Hillblom Foundation, and the Down Syndrome Research and Treatment Foundation (W.C.M.).
(Dorsey et al.)
The researchers include Susan G. Dorsey of the University of Maryland School of Nursing in Baltimore, MD (formerly of the National Cancer Institute in Frederick, MD); Cynthia Renn and Christopher W. Ward of the University of Maryland School of Nursing in Baltimore, MD; Linda Bambrick and Bruce K. Krueger of the University of Maryland, Baltimore School of Medicine in Baltimore, MD; Laura Carim-Todd, Colleen A. Barrick, and Lino Tessarollo of the National Cancer Institute in Frederick, MD.
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH grants K22NR00174-03 (S.G.D.), R01NS40492 (B.K.K.), and K01-AR02177 (C.W.W.).
Salehi et al.: "Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration." www.neuron.org
Dorsey et al.: "In Vivo Restoration of Physiological Levels of Truncated TrkB.T1 Receptor Rescues Neuronal Cell Death in a Trisomic Mouse Model." www.neuron.org
Related Preview by Castrén et al.: "Neurotrophins and Dementia--Keeping in Touch."