14 DAY TRIAL // 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 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 documenting this discovery were written by William C. Mobley and Ahmad Salehi of Stanford University, Susan G. Dorsey at the University of Maryland Baltimore School of Nursing and Lino Tessarollo of the National Cancer Institute.
In humans, Down's syndrome (DS) 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 (AD). More details on this here.
The researchers 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."
Moreover, 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.
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.
They found that neuronal cell death could be prevented 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.