22 Jul 2004

It has been said that Alzheimer’s disease is not about losing your car keys, but about having them in your hand and not knowing what they do. Such long-term memory (LTM) shortcomings are what we all fear most about this terrible disease. The question is: How do we make AD but a memory? To stabilize, or at least slow the memory losses associated with Alzheimer’s, it may be beneficial to know more about how long-term memory works. In this week’s Nature, Thomas Preat and colleagues at the CNRS, Gif sur Yvette, France, report that cramming may play a key role in Drosophila LTM. Not the cramming you would indulge in before a test, mind you, but cramming as in the activity of the protease inhibitor crammer.

First author Daniel Comas and colleagues homed in on the gene for crammer when they carried out screens to find mutations that hamper long-term memory in flies. Fruit flies can be trained to memorize certain smells, and subsequent exposure to the memory-jogging aroma elicits expression of genes in mushroom bodies, parts of the fly olfactory memory center. Comas and colleagues used a gene trap method to direct mutational inserts into genes expressed in these bodies. They found one mutant strain with only about half the long-term memory capacity of normal flies, a loss that was statistically significant.

The authors then pinpointed the mutation that caused the phenotype. They found the insert lay just downstream of the gene cer, and rescue experiments using wild-type cer confirmed that crammer, the product of the gene, is essential for normal LTM.

Crammer turns out to be highly similar to the inhibitory amino terminal of cathepsin L, which is synthesized as a proprotein. While chopping off the N-terminal turns inactive proprotein into active cathepsin, Comas found that the 79 amino acid crammer potently inhibited cathepsins L or B, even though it is not covalently attached. Crammer, it appears, is the first example of a cathepsin inhibitor that works in trans.

The results suggest that inhibition of cathepsins is necessary for acquiring long-term memory. As for Alzheimer's, cathepsins have been implicated in many different ways. D isoform polymorphisms were once thought to confer higher risk for AD, though there are now many more studies which question that link (see overview in our new Alzgene database), while cathepsins B and L have been associated with age-related lysosomal dysfunction (see Yong et al., 1999) and with neurofibrillary tangle formation in ApoE-deficient mice (see Bi et al., 2001). The authors are particularly intrigued by the association between prolonged proteinase activation with neuronal degeneration in AD. “Regions that contain maximal amounts of amyloid precursor protein also express maximal concentrations of cathepsin B and cathepsin L mRNA, indicating that the memory deficit of these patients might be linked to the deregulation of biochemical pathways involved in neuronal brain plasticity,” the authors write. They speculate that the memory deficit observed in flies lacking crammer might parallel this situation.—Tom Fagan