Inside Salk - October 2009 - page 21

The team, led by
FredH. Gage
, a
professor in the Salk’s Laboratory of
Genetics, found that human brain cells
contain an unexpected number of so-
calledmobile elements—extraordinary
pieces of DNA that insert extra copies of
themselves throughout the genome using
a “copy and paste”mechanism.
“This is a potential mechanism to cre-
ate the neural diversity that makes each
person unique,” says Gage. “The brain
has 100 billion neurons with 100 trillion
connections, but mobile pieces of DNA
could give individual neurons a slightly
different capacity from each other.”
In earlier work, Gage had already
shown that mobile pieces of DNA known
as LINE-1 elements (short for Long inter-
spersed element 1) randomly add extra
“Jumping Genes” Create Diversity
in Human Brain Cells
copies to the genome of mouse brain
cells. But whether or not the same pro-
cess, colloquially referred to as “jump-
ing,” held true for neurons in human
brains had been amatter of some debate.
When postdoctoral researcher and first
author
Nicole Coufal
measuredmatched
samples (brain versus other body tissues)
from numerous individuals, she found
that some brain samples had asmany as
100 extra copies per cell.
“This was proof that these elements
really are jumping in neurons,” explains
Coufal. Strikingly, it alsomeans that not
all cells are created equal—humans are
true chimeras since the DNA in their
brain cells is different from the DNA in
the rest of their cells.
Rather than sticking toa singleDNA script, human braincells
harbor astonishing genomic variability, according to Salk scientists.
The findings could help explain brain development and individuality,
aswell as lead toa better understandingof neurological disease.
Inside SalkOctober 2009
21
I N S T I T U T E N EWS
Nicotinic Receptor
May Help Trigger
Alzheimer’s Disease
Forclose toadecade, pharmaceutical
researchers have been in hot pursuit of com-
pounds to activate a key nicotine receptor that
plays a role in cognitive processes. Triggering
it, they hope, might prevent or even reverse the
devastationwrought by Alzheimer’s disease.
A new study from the Salk Institute, however,
suggests that when the receptor, alpha-7,
encounters beta amyloid, the toxic protein found
in the disease’s hallmark plaques, the twomay
actually go rogue. In combination, alpha-7 and
beta amyloid appear to exacerbate Alzheimer’s
symptoms, while eliminating alpha-7 seems to
nullify beta amyloid’s harmful effects.
These findings, reported recently in The Jour-
nal of Neuroscience, may shed new light on the
processes leading to Alzheimer’s and could have
important implications for researchers seeking
to combat the disease.
Intrigued by earlier studies showing that
beta amyloid seemed particularly drawn to
the alpha-7 nicotinic receptors, researchers in
the lab of
Stephen F. Heinemann
, in the Salk
Molecular Neurobiology Laboratory, sought
to determine whether the alpha-7 receptors
actuallymodulate the effects of beta amyloid
in Alzheimer’s disease.
Hypothesizing that the alpha-7 nicotinic
receptorsmediate beta amyloid effects in
Alzheimer’s disease, Heinemann’s team crossed
mice engineered to lack the gene for alpha-7
with amousemodel for Alzheimer’s disease,
which had been genetically engineered to
overexpress amyloid precursor protein (APP),
an antecedent to beta amyloid. They then put
the offspring through a series of memory tests.
Surprisingly, those with bothmutations—too
much APP and no gene for alpha-7—performed
as well as normal mice. The Alzheimer’smice,
however, which had the alpha-7 gene and also
overexpressed APP, did poorly on the tests.
Pathology studies revealed the presence of
comparable amounts of plaques in the brains
of both types of mice, but in those lacking the
alpha-7 gene, they appeared to have no effect.
Similar disparities were evident inmeasurements
of the synaptic function underlying learning
andmemory.
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