Enzyme Found that Puts the ‘Beta’ in Beta-Amyloid
December 1, 1999 4 minutes read
Enzyme Found that Puts the Beta’ in Beta-Amyloid
Abstract & commentary
Source: Vassar R, et al. Beta-secretase cleavage of Alz-heimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735-741.
In light of the importance of amyloid in the neuropathology of Alzheimer’s disease (AD), an intense search for the enzymes involved in the processing of beta-amyloid (b-amyloid) has been under way for more than a decade. Researchers at Amgen, a California-based biotechnology company, have now succeeded in isolating one of the key enzymes involved in b-amyloid production. The enzyme they discovered is a b-secretase that creates the beta end (amino terminus) of the b-amyloid molecule by cleaving the membrane-bound amyloid precursor protein (APP).
Vassar and colleagues found this long-sought enzyme by using a strategy known as expression cloning. They worked with human embryonic kidney cells that contain a mutant form of the APP molecule and overproduce b-amyloid. They then searched for the genes that modulated b-amyloid production. They identified one such gene that encoded a novel protein that resembled a known class of aspartic proteases, making it a plausible candidate for b-secretase.
Vassar et al then demonstrated that this protein, which they now call the beta-site APP-cleaving enzyme (BACE), had all of the expected characteristics of b-secretase. Amyloid is produced throughout the body, and most tissues were found to express modest levels of BACE messenger RNA (mRNA). Slightly higher levels were present in the brain and highest levels were found in the pancreas. The processing of APP is known to take place in intracellular membranous compartments, and the BACE protein was found to be membrane bound. BACE mRNA was found in neurons but not glial cells, once again consistent with the expected localization of b-secretase. The highest levels of BACE protein-related immunoreactivity were found in the Golgi bodies and endosomes, the intracellular compartments where b-cleavage of APP is thought to take place.
In further studies, it was demonstrated that overexpression of BACE led to an increase in b-amyloid production but did not influence production of APP or the cleavage of the carboxy terminus of the amyloid molecule. It was also shown that purified BACE specifically cleaved the APP molecule at the precise position required to generate b-amyloid. These and other experiments leave little doubt that the BACE protein is b-secretase, one of the long-sought molecular prizes of Alzheimer’s research.
Commentary
This report provides convincing evidence that a real b-secretase has finally been found. Other investigators have identified candidate molecules with some of the expected properties of a b-secretase, but the findings have never been as strong as in the case of BACE. Indirect evidence was recently published that another Alzheimer-related protein called presenilin may be g-secretase, the enzyme responsible for cleaving the carboxy-terminus of the b-amyloid molecule. If it turns out that presenilin does not play this role, then perhaps the expression cloning strategy used in the discovery of BACE will also yield fruit in isolating the true g-secretase.
The discovery of BACE has potential therapeutic implications. Even before BACE was identified, several pharmaceutical companies had already characterized compounds that nonspecifically reduce b-amyloid production through the inhibition of b-secretase-like activity in cell cultures. The discovery of BACE should permit accelerated characterization of these compounds, as well as the engineering of entirely new agents that more specifically inhibit this b-secretase. The viability of using protease inhibitors in the treatment of human disease has been already been demonstrated in the context of treating HIV infection. The identification of an aspartic protease that has all of the expected characteristics of b-secretase makes it likely that protease inhibition will be studied as a potential approach to the treatment and prevention of AD.
It may be premature, however, to extrapolate from this discovery to a future treatment of AD. There is still some uncertainty about whether amyloid production and/or accumulation actually causes AD, and there is no proof that decreasing b-amyloid production will arrest the incidence or progression of the disease. A direct test of this hypothesis should soon be possible through clinical trials of agents that inhibit b-secretase. —nrr
The expected characteristics of b-secretase include all of the following except:
a. cleavage of the carboxy terminus of the amyloid precursor protein (APP).
b. activity present in the brain as well as other organs.
c. enzyme present in neurons but not in glia.
d. enzyme present in the intramembranous compartment.
Vassar and colleagues found the enzyme BACE by using expression cloning.
a. True
b. False
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