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Potential
Alzheimer’s Disease drug target identified
Newswise — In findings
with the potential to provide a therapy for
Alzheimer’s disease patients where none now
exist, a researcher at the University of
California, San Diego and colleagues have
demonstrated in mice a way to reduce the
overproduction of a peptide associated with
the disease.
The study, which showed
substantial improvement in memory in an
animal model of Alzheimer’s disease, was led
by Vivian Y. H. Hook, Ph.D., professor of
the Skaggs School of Pharmacy and
Pharmaceutical Sciences and professor of
neurosciences, pharmacology and medicine at
the UCSD School of Medicine, together with
American Life Science Pharmaceuticals of San
Diego.
A hallmark sign of
Alzheimer’s disease, seen during autopsy of
a patient’s brain, is the accumulation of
amyloid plaque deposits composed primarily
of the neurotoxic beta-amyloid (Aβ) peptide
which is believed to be a major factor in
the cause of the disease.
The Aβ peptides are
“cut” out from a larger protein called the
amyloid precursor protein (APP) and bind
together to form plaques in brain regions
responsible for memory. One drug strategy to
fight Alzheimer’s disease is to reduce
production of Aβ.
"We discovered two
chemical compounds that inhibit a new enzyme
target, leading to reduced production of
beta-amyloid and improved memory in a mouse
model of Alzheimer’s disease,” said Hook.
Accumulation of Aß and
plaque build-up are initiated when the large
precursor protein, APP, a long string of
amino acids, is “cut” into the smaller,
neurotoxic Aβ peptides that generate amyloid
plaques. Protease enzymes, a type of
protein, are the “scissors” that cut the
large APP to generate Aβ peptides.
The protease must cut
the APP amino acid sequence in two places:
at the beta-secretase and the gamma-secretase
sites. In this study, by inhibiting and
therefore preventing the enzymatic
“scissors” from “cutting” the APP chain into
smaller peptides, the research team observed
improved memory, as well as reduced levels
of beta-amyloid protein in the brain, in
mice bred to exhibit Alzheimer’s disease
symptoms.
In the past, many
scientists have focused on a mutant beta-secretase
sequence only seen in one extended family of
patients in Sweden with Alzheimer’ disease,
Hook explained.
This mutation, the so-called
Swedish mutation, was known to result in an
overproduction of Aβ. Past research has
shown that this Swedish mutant sequence is
cut by a protease called BACE1.
Hook and colleagues
found that a different protease, called
Cathepsin B (CatB) works to cut the normal
beta-secretase site – which is the site
present in more than 99 percent of patients
with Alzheimer’s disease – but not the
Swedish mutant site. They also tested
compounds that inhibit CatB – E64d and
CA074Me –in a mouse model of Alzheimer’s
disease with the normal beta-secretase site.
“After drug treatment,
using water maze memory tests, we found that
the mice exhibited great improvement in
their memory, as well as reduced brain
levels of beta amyloid,” said Hook.
“These
results are consistent with previous
research indicating that CatB is elevated in
brains of patients with Alzheimer’s
disease.”
She added that a drug
that duplicates this reduction by targeting
CatB in humans could be an effective
treatment for Alzheimer’s disease in the
more than 99 percent of individuals with the
normal beta-secretase site.
“By disabling
the enzyme’s ability to cut the ‘beta’ end
of the amino acid sequence, researchers may
discover a way to limit production of neurotoxic Aβ and reduce amyloid plaques in
the brain.”
Additional contributors
to this study are Gregory Hook, Ph.D.,
American Life Science Pharmaceuticals, San
Diego, which is engaged in developing drugs
based on this new target; and Mark Kindy,
Applied Neurotechnology Inc. Charleston, SC.
Funding was provided by the National
Institute of Aging, NIH.
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