Sci. Aging Knowl. Environ., 7 April 2004
Proteins implicated in Alzheimer's disease also coddle brain cells
To stem the damage from Alzheimer's disease, researchers hope to slice the supply of amyloid, a protein that fouls the brains of AD patients. But new work suggests that eliminating two proteins that help make amyloid undermines long-term memory and incites brain deterioration. The finding raises questions about the safety of anti-AD drugs that curtail the production of amyloid.
The presenilin proteins band together with other proteins to form molecular scissors known as -secretase, which frees amyloid from its precursor. Patients with rare, inherited forms of AD carry altered presenilins that generate unusually large amounts of a particularly insidious version of amyloid. The standard explanation is that the mutant presenilins cause illness by pumping out more of the nasty amyloid, says molecular neurobiologist Jie Shen of Harvard Medical School in Boston. But faulty presenilins might fail to perform an unidentified beneficial task, thus spurring brain deterioration. Testing the idea is crucial because drug companies have already started trials of anti-AD drugs that shackle presenilins. However, divining other jobs performed by presenilins is difficult because disrupting the genes in embryonic mice is lethal.
So Shen and colleagues disabled the genes only in mouse forebrains, which help etch memories. At the age of 2 months, the rodents performed worse than controls on two standard recall tests. As the mice grew older, their memory declined, and their brains began to degenerate. In animals between 6 and 9 months old, almost one-quarter of the neurons in one section of the forebrain had perished.
Next, the researchers tried to home in on molecular pathways altered by the absence of presenilins. They examined the NMDA receptor; activating this cell-membrane molecule increases brain synapses' sensitivity and promotes learning. The receptor and other molecules stimulate genes that help solidify long-term memories and keep brain cells alive. Losing presenilins slashed the activity of two of these genes by more than 50% and trimmed the amount of NMDA receptor--declines that might explain the rodents' shaky memory. Taking away presenilins also hiked amounts of the noxious form of tau, another protein that builds up in AD (see "Detangling Alzheimer's Disease"). The results suggest that lack of presenilins harms neurons by slashing the activity of nurturing genes and inflating the amount of toxic tau. In some forms of inherited AD, faulty presenilins might cause brain deterioration directly, not just by producing amyloid.
The discovery that removing presenilins provokes brain deterioration is "striking," says neuroscientist Weihong Song of the University of British Columbia in Vancouver, Canada. The finding suggests that blocking presenilins to disrupt -secretase might cause trouble, Song says, although perhaps researchers can craft drugs that eliminate one presenilin function without hampering others. The study delivers a stronger message, says neuroscientist Todd Golde of the Mayo Clinic in Jacksonville, Florida. Several side effects of -secretase inhibitors have already come to light, so the results are "another nail in the coffin" for the strategy. Researchers might have to find a new way to cut off the source of amyloid.
April 7, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150