11 November 2001. The β-secretase enzyme BACE1 become an instant favorite
among researchers interested in developing small-molecule drugs against
Alzheimer's disease when it was cloned by researchers at Amgen and even more so when its crystal structure was solved shortly afterwards. BACE1 is an
aspartyl protease, as is HIV protease, so the pharmaceutical industry can
draw on abundant prior experience in structure-based drug design against
this class of enzyme.
Similarly, much excitement greeted the still somewhat controversial
identification of γ-secretase, and inhibitors of this aspartyl protease have made their way into early clinical trials. Lately, however, γ-secretase has lost some of its luster as follow-up basic research identified additional substrates. Including notch and others, these targets raise concerns about side effects of γ-secretase inhibition and make designing a drug that hits
one γ-secretase activity but spares the others a tricky business (see, for
example, related news item.)
Will a similar fate befall BACE1? Unlikely, says Philip Wong of John's
Hopkins University, Maryland. Today at the Neuroscience meeting, Wong, working with
Don Price and others, presented data that appear to make BACE1 an even more
appealing target. In one study, Wong asked why only brain is prone to
develop amyloidosis when all cells of the body process AβPP. His group found that BACE1 is much more abundant in brain than in non-neural tissues.
Studies in mice show that BACE1 is highly expressed in hippocampus,
olfactory bulb and posterior cortex, areas affected in AD, but not in the
cerebellum, a motor and balance-control region less damaged in AD. At the
same time, high BACE1 was coupled with low levels of BACE2 (which acts more
like α-secretase in that it limits Aβ generation), whereas low levels of
BACE1 and high levels of BACE2 were seen in non-neural cells, such as
Moreover, Wong's group has crossed a BACE1 knockout into PS1+APP transgenic
mice to address the question whether partial BACE1 inhibition might be
sufficient to slow plaque formation. The researchers presented data showing
that a heterozygous BACE1 knockout, which still produces 50 percent of the
normal BACE1 protein levels, led to marked reduction of plaques and soluble
Aβ levels in this mouse model of amyloid deposition. The homozygous BACE1
knockout/PS1+APP transgenic mice had no detectable Aβ, Wong said in a press
When localizing BACE1 in mouse hippocampal neurons, Wong et al. found it in
the dystrophic terminal dendrites that surround mature amyloid plaques.
Interestingly, Yong Shen of the Sun Health Research Institute in Sun City,
Arizona, who recently succeeded in isolating and culturing living neurons
from rapidly autopsied AD brains, also detected endogenous BACE1 in the
terminals of those neurons.
In related news, M.J. Chiocco and Bruce Lamb of Case Western Reserve University
in Cleveland, Ohio, report the development of a new tool to study the role of
BACE1 and BACE2 in AβPP processing and Aβ
deposition. These researchers created genomic-based BACE1 transgenic mice that
overexpress human BACE1 mRNA and protein and crossed these with APP transgenic
mice. These mice should grossly overproduce Aβ. Wong
noted that some evidence indicates that BACE1 activity increases in humans with
age, suggesting that whatever causes this increase could contribute to late-onset
Caveats remain. While the finding that BACE1 knockout mice are viable and
appear to develop largely normal bodes well for drug discovery, BACE2 might
still turn out to have essential substrates whose inhibition could be
deleterious. This question awaits the generation of BACE1/BACE2 double
knockout mice.-Gabrielle Strobel.
Reference:Wong PC et al. BACE1 protein is most abundant in neurons: a determinant of
Ab amyloidosis. Soc Neuroscience 2001.
Cai H et al. b-secretase (BACE1) and modulation of Ab amyloidosis in
Alzheimer's disease. Soc Neuroscience 2001. Abstract
Yan X, et al. Endogenous expression of b-secretase in isolated living
neurons from Alzheimer's brains and APP transgenic mouse brains. Soc Neuroscience 2001.
Chiocco MG, Lamb BT. Soc Neurosci 2001.