Gene mutation defends against Alzheimer's disease.
ABSTRACT Rare genetic variant suggests a cause and treatment for cognitive
- SourceAvailable from: Wolfgang Froestl[Show abstract] [Hide abstract]
ABSTRACT: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years.Journal of Alzheimer's disease: JAD 10/2012; · 3.61 Impact Factor
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ABSTRACT: Beta-secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-beta peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of non-peptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity.Journal of Medicinal Chemistry 02/2013; · 5.48 Impact Factor
BY EWEN CALLAWAY
expected to quadruple by 2050. Yet doctors
can offer no effective treatment, and scientists
have not been able definitively to pin down the
underlying mechanism of the disease.
Research published this week offers some
hope on both counts, by showing that a lucky
few people carry a genetic mutation that natu-
rally prevents them from developing the con-
dition1. The discovery not only confirms the
principal suspect that is responsible for Alzhei-
mer’s, it also suggests that the disease could be
an extreme form of the cognitive decline seen
in many older people. The mutation — the first
ever found to protect against the disease — lies
in a gene that produces amyloid-β precursor
protein (APP), which has an unknown role in
the brain and has long been suspected to be at
the heart of Alzheimer’s.
APP was discovered 25 years ago in patients
with rare, inherited forms of Alzheimer’s that
strike in middle age2–5. In the brain, APP is
broken down into a smaller molecule called
amyloid-β. Visible clumps, or plaques, of
amyloid-β found in the autopsied brains of
patients are a hallmark of Alzheimer’s, but sci-
entists have long debated whether the plaques
are a cause of the neuro degenerative condi-
tion or a consequence of other biochemical
changes associated with the disease. The latest
finding supports other genetics studies blam-
ing amyloid-β, and it makes the protein “the
prime therapeutic target”, says Rudolph Tanzi, a
neurologist at the Massachusetts General Hos-
pital in Boston and a member of one of the four
teams that discovered APP’s role in the 1980s.
If amyloid-β plaques were confirmed as
the cause of Alzheimer’s, it would bolster
efforts to develop drugs that block their
formation in order to treat or prevent the rav-
aging condition, says Kári Stefánsson, chief
executive of deCODE Genetics in Reykja-
vik, Iceland, who led the latest research. He
and his team first discovered the mutation
by comparing the com-
plete genome sequences
of 1,795 Icelanders with
their medical histories.
The researchers then
studied the variant in
lmost 30 million people live with
Alzheimer’s disease worldwide, a
staggering health-care burden that is
nearly 400,000 more Scandinavians.
The variant is rare, but it has a huge impact
on those fortunate enough to inherit even a
single copy of it. About 0.5% of Icelanders are
carriers, as are 0.2–0.5% of Finns, Swedes and
Norwegians. Compared with their countrymen
who lack the mutation, Icelanders who carry it
are more than five times more likely to reach
85 without being diagnosed with Alzheimer’s.
They also live longer, with a 50% better chance
of celebrating their 85th birthday.
The mutation seems to put a brake on the
milder mental deterioration that most elderly
people experience. Carriers are about 7.5
times more likely than non-carriers to reach
the age of 85 without suffering major cogni-
tive decline, such as memory loss. They also
perform better on the cognitive tests that are
administered thrice yearly to Icelanders who
live in nursing homes.
For Stefánsson, this suggests that Alzhei-
mer’s disease and cognitive decline are two
sides of the same coin, with a common cause
— the build-up of amyloid-β plaques in the
brain, something seen to a lesser degree in
elderly people who do not develop full-blown
Alzheimer’s. “Pathologists have always sus-
pected that there was a substantial overlap
between Alzheimer’s disease and normal age-
related changes,” says Stefánsson. A drug that
mimics the effects of the mutation, he says,
would have the potential both to slow cogni-
tive decline and to prevent Alzheimer’s.
Stefánsson and his team discovered that
the mutation introduces a single amino-acid
alteration to APP. This amino acid is close to
the site where an enzyme called β-secretase 1
(BACE1) ordinarily snips APP into smaller
amyloid-β chunks — and the alteration is
enough to reduce the enzyme’s efficiency.
Blocking BACE1 to treat Alzheimer’s is not a
new idea. Drug companies have been working
on ‘BACE inhibitors’ for more than a decade,
and several are now in clinical trials. Stefánsson’s
study suggests that blocking β-secretase from
cleaving APP does indeed have the potential to
prevent Alzheimer’s, says Philippe Amouyel,
an epidemiologist at the Pasteur Institute in
Lille, France. But “it is very difficult to identify
the precise time when this amyloid toxic effect
could still be modified”, he warns. “If this effect
needs to be blocked as early as possible in life
to protect against Alzheimer’s disease, we will
need to propose a new design for clinical trials”
to identify an effective treatment.
Julie Williams, an expert on the genetics of
Alzheimer’s disease at Cardiff University, UK,
agrees that amyloid-β is strongly implicated by
the latest research, but adds that “it still doesn’t
say it’s the only factor we should be targeting,
in terms of therapies”.
For Stefánsson, the results are also a pow-
erful demonstration that whole-genome
sequencing can uncover very rare mutations
that nonetheless offer insight into common
diseases. He argues that most human differ-
ences, including disease risk, are determined
by common genetic variants that each tilt the
odds of developing a disease only slightly.
Rarer mutations, by contrast, tend to skew
someone’s disease risk much more strongly, but
only in a handful of patients. “The rare vari-
ants are not going to explain a large amount
[of disease], but they are going to provide very
key mechanistic insights into how all of this
happens,” says Stefánsson. He and his team
will soon publish studies on rare variants that
influence the risk of other conditions, includ-
ing ovarian cancer and gout. “We are going to
see a lot of these,” he says. ■
1. Jonsson, T. et al. Nature http://dx.doi.org/10.1038/
2. Kang, J. et al. Nature 325, 733–736 (1987).
3. Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti,
U. & Gajdusek, D. C. Science 235, 877–880 (1987).
4. Robakis, N. K., Ramakrishna, N., Wolfe, G. &
Wisniewski, H. M. Proc. Natl Acad. Sci. USA 84,
5. Tanzi, R. E. et al. Science 235, 880–884 (1987).
Gene mutation defends against
Rare genetic variant suggests a cause and treatment for cognitive decline.
Read more in
Nature’s Outlook on
About 0.5% of Icelanders have a protective gene
that prevents mental deterioration in old age.
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