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Destroying the plaque-forming beta amyloid peptides is a key strategy in developing Alzheimer's therapeutics, because most researchers are betting that the disease stems from an excess of the beta amyloid peptides. If the amyloid hypothesis is correct, approaching the problem from the other side of the equation – preventing plaque from building up by stopping the production of the peptides – should also work.

Pharmaceutical companies were initially excited by the prospect of stopping peptide production by inhibiting an enzyme named gamma-secretase, believed to be a large, multimeric protein complex that contains presenilin. But as more of substrates for this enzyme were discovered, researchers are worried that inhibition could also adversely affect the immune system.

Drug developers may now be able to put aside their fears of this side effect, however, as a result of new findings from Columbia researchers that show how inhibiting only presenilin could prevent beta amyloid production without disturbing the growth of white blood cells essential for a healthy immune system.

But the researchers, led by Dr. Nikolaos Tezapsidis at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, say another activity of presenilin may also prevent plaque formation by helping to bring beta amyloid peptides into the cell. If such uptake by cells protects the brain by removing the beta amyloid from extracellular spaces, blocking presenilin may still have unwanted consequences. The research was published May 8 on the FASEB Journal Web site.

Though it's associated with a disease of aging, beta amyloid is produced in most of the body's cells throughout life from a larger protein, amyloid precursor protein (APP). Two distinct enzyme activities snip beta amyloid peptides out of APP: beta-secretase first cuts at a site outside the membrane, and then gamma-secretase cuts at a location within the membrane. Depending on exactly where gamma-secretase snips, it can produce a peptide with 40 amino acids – which appears to be harmless – or the 42-amino acid peptide, which clumps into plaques outside the neurons.

The presenilin protein is absolutely essential for the second cut by gamma-secretase, but presenilin is also crucial for the processing of the Notch protein, which is very active both during development and during adult processes such as white blood cell production.

Dr. Tezapsidis' new work shows that presenilin's interaction with a microtubule protein in neurons could lead to finding a presenilin inhibitor that doesn't act on Notch. He found beta amyloid peptides are produced only if presenilin binds to CLIP-170, a protein that attaches organelles to microtubules for transport within the cell. Blocking presenilin and CLIP binding stopped beta amyloid production but had no effect on the processing of Notch.

In an unexpected twist, Dr. Tezapsidis and his colleagues found that presenilin-CLIP interaction is also required for the cell's uptake of beta amyloid from outside the cell. "The uptake may be a way that the cell clears beta amyloid from the extracellular spaces where the peptide accumulates into plaques," Dr. Tezapsidis says. "Therefore, preventing presenilin and CLIP from binding may block a beneficial clearing mechanism."

The two jobs of presenilin and CLIP – beta amyloid formation and beta amyloid uptake – present a dilemma: Preventing their interaction would reduce the formation of beta amyloid but would also decrease the uptake of beta amyloid. What to do next will depend on figuring out what the cell's intake of beta amyloid accomplishes. "If beta amyloid uptake is a bad guy, we should go ahead and inhibit presenilin," Dr. Tezapsidis says.

Answering the question of whether amyloid uptake is a bad guy or good guy may be made easier by considering other data from the study that confirmed the role of apolipoprotein E (ApoE) in the uptake. ApoE binds to beta amyloid before the two are brought into the cell, but possessing one version of the protein, 4, is known to increase a person's risk of developing Alzheimer's. Whether the increased risk comes from 4 bringing more or less beta amyloid into the cell is still unknown, but knowing presenilin is involved may lead to an answer.

The research was funded by the Alzheimer's Association.


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