Cause of neuronal death in Down's syndrome, Alzheimer's disease could be surprisin...( n in the context of a complex genetic l...)

n 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)
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
5-Jul-2006

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