ASCB 2013 PressBook - page 4

T H E A M E R I C A N S O C I E T Y F O R C E L L B I O L O G Y
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4
News from
The American Society
for Cell Biology
53rd Annual Meeting
New Orleans, LA
December 14–18, 2013
A delicate balance disturbed
EMBARGOED
FOR RELEASE
10:00 am, U.S. Central Time
Sunday, December 15, 2013
Contact
George S. Bloom
University of Virginia
Dept. of Biology
PO Box 400328
Charlottesville, VA 22904-3543
(434) 243-3543
Author Presents
Sunday, December 15, 2013
12:00 PM–1:30 PM
Rho-Family GTPases
Presentation 614
Poster B1117
Exhibit Halls B–D
Ectopic Cell Cycle Re-entry, a
Major Cause of Neuron Death in
Alzheimer’s Disease, Is Con-
trolled by Rac1 and mTOR
A. Norambuena, L. McMahon,
E. Kodis, G.S. Bloom
Department of Biology, University
of Virginia, Charlottesville, Virginia
The Bloom lab’s work on CCR
has been generously supported
by the Owens Family Founda-
tion, the Alzheimer’s Association
(grant 4079), and NIH/NIGMS
training grant T32 GM008136.
All of the proteins and biochemical connections that are
currently known to be required for A
b
oligomer-induced,
tau-dependent cell cycle re-entry (CCR) and neuron
death are shown here.
CaMKII,
fyn
and
PKA
are
protein
kinases
that respectively phosphorylate
tau
at amino
acids 416 (
pS416
), 18 (
pY18
) and 409 (
pS409
). The
pathway highlights many potential new early biomarkers
and therapeutic targets for Alzheimer’s disease.
Uncovering the first molecular
missteps that drive neurons into the
pathway of cell cycle re-entry and
lead to Alzheimer’s disease
D
ramatic stories in cell biology often
have sequels—“Duel of the Alzheim-
er’s Proteins, Part XV”—and indeed
this work is a nail-biting sequel to George
Bloom’s hypothesis that interaction between
amyloid-beta peptides and the protein tau
drives adult neurons into the forbidden
pathway of “cell cycle re-entry” (CCR). The
long-term result is Alzheimer’s disease (AD).
Bloom and colleagues at the University of
Virginia (UVA) now say that they have found
the critical balance point between tau and a
master cellular regulator that amyloid-beta
oligomers disrupt.
As reported at last year’s ASCB Annual
Meeting
2012_Pressbook/2012Pressbook/#4)
, Bloom
says that most normal adult neurons are
supposed to be permanently postmitotic;
that is, they have finished dividing and are
locked out of the cell cycle. Yet in Alzheim-
er’s, neurons frequently re-enter the cell cy-
cle, fail to complete mitosis, and ultimately
die. In late stage AD, up to 30 percent of the
neurons in the frontal lobes of the brain are
dead, surrounded by large amyloid plaques
and tau-associated neurofibrillary tangles.
Much of the debate in AD research has
been about which protein—amyloid-beta or
tau— is the symptom and which the cause,
but Bloom and his UVA colleagues have
moved in a different direction. They see
AD as a problem of the cell cycle, with both
amyloid-beta and tau required for the inter-
action that pushes neurons into destructive
CCR. “The massive neuron death that oc-
curs in AD therefore appears to be caused by
the raw ingredients of plaques and tangles
working in concert with each other, rather
than by the plaques and tangles themselves,”
Bloom explains.
Last spring, the UVA researchers de-
scribed in greater detail
how
amyloid-beta activates multiple enyzmes
called protein kinases to add phosphates to
specific sites on tau, setting neurons on the
pathway to CCR. Now in this new molecular
“sequel,” Andrés Norambuena, Lloyd McMa-
hon, and others in the Bloom lab implicate
a novel group of proteins— Rac1, Gs
α
, and
NCAM—and two protein kinases complex-
es—mTORC1 and mTORC2—as required
participants to set off CCR.
Their identification reveals how a
fundamental balance is upset, placing
neurons on the road to AD. “The mTOR
complexes are master regulators of cellular
proliferation, growth, and metabolism,”
Bloom explains. “Most importantly, our
results indicate that tau normally inhibits
mTOR from promoting neuronal cell rep-
lication, but that this inhibition is reversed
by an amyloid beta oligomer-induced,
mTOR-dependent mechanism that modi-
fies tau. In other words, tau and mTOR
regulate each other.”
This delicate balance is compromised
by amyloid-beta oligomers in a way that
allows neurons that should never replicate
to re-enter the cell cycle. They fail to di-
vide and eventually die instead. “Some of
the earliest events in AD pathogenesis are
therefore caused by amyloid-beta oligo-
mers altering a fundamental neuronal
signaling axis centered around tau and
mTOR,” Bloom proposes. He believes that
the proteins identified in this signaling axis
are potential biomarkers and therapeutic
targets for very early stages of AD, leaving
the door open for an even more exciting
sequel down the road.
I,II,1,2,3 5,6,7,8,9,10,11,12,13
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