Scientists have discovered a genetic abnormality that may figure importantly in understanding a range of neurodegenerative diseases such as Down's Syndrome and Alzheimer's.

Two studies -- one led by William C. Mobley and Ahmad Salehi of Stanford University and the other conducted by Susan G. Dorsey at the University of Maryland Baltimore School of Nursing and Lino Tessarollo of the National Cancer Institute -- offer new hope for treatments to combat these and related disorders.

Their findings are published in the journal Neuron.

Increase in Expression of a Single Gene

Some 350,000 Americans have Down's syndrome, which is often accompanied by mental retardation and the risk of premature onset of Alzheimer`s disease.

In humans, Down's syndrome is caused by a trisomy -- an abnormal three copies of chromosome 21 that causes an increased "dosage" of genes on that chromosome. A central mystery of Down's syndrome is how such an overdose of particular genes leads to abnormalities such 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. found that an increase in the expression of only one gene -- for amyloid precursor protein (APP) -- disrupts transport of the neurotrophin "nerve growth factor." 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.

Path Toward Treatment Suggested

In their studies, Salehi et al. 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 nerve growth factor 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 "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 (basal forebrain cholinergic neurons). If so, treatments to reduce APP gene expression may prove valuable."

Cause or Effect?

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, 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."