Cause of neuronal death in Down's syndrome, Alzheimer's disease could be surprisin...( ular levels of a Trk receptor for the n...)

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