Inactivation of Alzheimer's disease genes in mice causes dementia and brain de...( Using advanced genetic engineering tech...),Health

Using advanced genetic engineering technology, scientists have discovered that deletion of two related genes linked to inherited forms of Alzheimer's disease causes memory loss and gradual death of nerve cells in the mouse brain. The researchers identified the molecular pathways through which inactivation of these genes in mice produces abnormalities strikingly reminiscent of Alzheimer's disease. The study, reported online in Neuron, may provide a new way to look at the cause of Alzheimer's disease, as it shows that the protein products of these Alzheimer's disease genes are essential for normal learning, memory and nerve cell survival. Furthermore, these results suggest that current therapeutic avenues of research designed to block the function of these genes may actually be detrimental.

Alzheimer's disease is a debilitating illness affecting 5 million Americans, with annual health care cost in excess of $100 billion. Mutations in the presenilin genes are the major cause of early onset, inherited forms of Alzheimer's disease (hence designated as "pre-senile" genes), but how these mutations cause the disease has not been clear. Since presenilins are involved in the production of amyloid peptides, the major components of amyloid plaques in the Alzheimer's disease brain, it was generally believed that genetic alterations in presenilins cause the disease by increasing brain levels of the particularly toxic form of amyloid peptides. Identification of compounds that can block presenilin function, therefore, has been a major therapeutic effort for combating Alzheimer's disease.

The research team, led by Dr. Jie Shen of Brigham and Women's Hospital and Harvard Medical School, created a unique mouse model that allowed them to examine the consequences of blocking presenilin function in the adult brain. Surprisingly, although the production of amyloid peptides was markedly reduced, these mutant mice nevertheless developed severe dementia and progressive
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
1-Apr-2004

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