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.