11 November 2001. There are two principal ways by which the Aβ
accumulation seen in the brains of people with AD can occur. One-overproduction
by β- and γ-secretases-has
received far more attention than the other-insufficient clearance of the offending
protein. That is now changing as more researchers are focusing on the fact that
the known mutations in APP and presenilin-1 and -2, all of which increase Aβ
production, account for only a small fraction of overall AD cases and for none
of the most common, late-onset form of the disease (LOAD). Gradually, the idea
that defects in neural proteases might underlie some cases of AD is gaining currency.
ApoE4, the only established genetic risk factor for LOAD, possibly impairs Aβclearance,
but by itself the contribution of this polymorphism to AD onset is estimated to
be no more than nine percent (Daw et al., 2000.)
A poster presented today by Wesley Farris, et al., at Brigham and Women's
Hospital, Boston, presents the latest data in an emerging story on Aβ degradation. It picks up on previous research suggesting that the major protease degrading (at least soluble, monomeric) Aβ insulin-degrading
enzyme (IDE) (Vekrellis et al. 2000). This metalloprotease actually cleaves
numerous substrates besides insulin, including glucagon and TGF-α. To learn
what IDE does in human brain, Farris et al. quantified Aβ degradation in total brain homogenates and in membrane fractions. They found that IDE accounted for 90 percent and 70 percent, respectively, of Aβ degradation.
The other significant protease in this experiment was neprilysin. (Young
neprilysin knockout mice have slightly increased Aβ levels but do not form plaques, suggesting that another protease can partially compensate for the loss of neprilysin, see related news item). Farris, who works with Dennis Selkoe and
colleagues, also reports that overexpressing IDE in cultured neurons lowered
endogenous Aβ levels; conversely, depleting IDE increased Aβ levels. IDE
knockout mice are currently being bred for analysis.
Next, the scientists analyzed Aβ degradation in cell lines established from AD families who are known to have a linkage to an area on the long arm of chromosome 10 (10q) that includes the IDE gene. This genetic connection
emerged, together with a second one in a nearby region also on 10q, in a
triplet of Science papers last December that implicated IDE and the protease
urokinase-type plasminogen activator (uPA) as candidate genes for LOAD.
(Neprilysin is located on chromosome 3.)
At this meeting, Farris et al. are reporting preliminary data on one family
with strong 10q linkage in whose cells the scientists were able to detect
decreased Aβ degradation.
Researchers in Rudolph Tanzi's lab at Massachusetts General Hospital, Boston, who collaborate with the Selkoe on this question, are searching for mutations in the IDE gene that would decrease its function. Also today, Lars Bertram in Tanzi's lab reported some progress in further characterizing the 10q locus, including five previously unknown polymorphisms in IDE that are currently being analyzed, but at present it remains unclear whether IDE is one of the two sought-after genes on chromosome 10. However, Farris says
that even if it is not, there is now enough data to suggest that increasing
IDE activity, perhaps by blocking its natural inhibitors, could one day
become a promising therapeutic strategy.-Gabrielle Strobel.
Farris RW et al. Insulin-degrading enzyme as the principal Aβ-degrading protease in human brain: Search for a genetic link to AD. Soc Neuroscience 2001.
Bertram L et al. Further characterization of the Alzheimer's disease locus on chromosome 10. Abstract 127.3.
Selkoe DJ. Clearing the brain's amyloid cobwebs. Neuron 2001,
October 25(32) 177-180. Abstract
Tanzi RE, Bertram L. New frontiers in Alzheimer's disease genetics. Same
issue of Neuron:181-184. Abstract