Temporal Profile of Amyloid-? (A?) Oligomerization in
an in Vivo Model of Alzheimer Disease
Salvatore Oddo‡, Antonella Caccamo‡, Levina Tran‡, Mary P. Lambert§, Charles G. Glabe¶, William L. Klein§,
and Frank M. LaFerla‡1
Evanston, Illinois 60208
Accumulation of amyloid-? (A?) is one of the earliest molecular
to be a later downstream event. It is now well established that A?
exists as monomers, oligomers, and fibrils. To study the temporal
profile of A? oligomer formation in vivo and to determine their
interaction with tau pathology, we used the 3xTg-AD mice, which
nitive impairments. We show that SDS-resistant A? oligomers
accumulate in an age-dependent fashion, and we present evidence
to show that oligomerization of A? appears to first occur intraneu-
a specific oligomeric antibody is sufficient to clear A? pathology,
play a role in the induction of tau pathology, making the interfer-
ence of A? oligomerization a valid therapeutic target.
order, affecting ?5 million Americans (1). Neuropathologically, it is
characterized by the accumulation of extracellular plaques, mainly
comprised of a small peptide called amyloid-? (A?), and intracellular
tau protein (2). Based on compelling genetic evidence, it has been pos-
tulated that pathological assemblies of A? are the cause of all forms of
a downstream consequence of the pathological accumulation of A?
initiates the neurodegenerative process, however, remains unknown.
Traditionally, A? has been viewed as being generated and secreted
extracellularly, but it is also becoming increasingly apparent that some
A? can be generated in different intracellular compartments, such as
is mounting evidence to support a pathophysiologic role for intracellu-
lar A? in AD an Down syndrome (see Ref. 12 for review).
A? exists in several different physical states, including as monomers,
oligomers, or fibrils. Evidence from in vitro studies demonstrates that
oligomers, which eventually may form fibrils (13–15). During the last
decade, in vitro and in vivo experimental evidence points to soluble A?
oligomers, also referred to as A?-derived diffusible ligands, as the pre-
dominant neurotoxic species for neurons (16, 17). In this regard, A?
oligomers are very potent toxic species, as even nanomolar concentra-
tions have been shown to kill mature neurons in hippocampal slices
(18). Moreover, A? oligomers appear to interfere with many critical
organotypic hippocampal slices (18, 19). A? oligomers can also cause
calcium dysregulation and membrane disruption, thus interfering with
overall cell functioning (20, 21). The toxicity of A? oligomers has also
been shown in vivo. In particular, intracerebroventricular injection of
oligomers inhibits LTP (22) and specifically disrupts cognitive function
(23). Importantly, the concomitant injection of the anti-A? antibody
6E10 with A? oligomers neutralizes the oligomer-induced LTP dys-
function (24). These data strongly support the idea that oligomers rep-
resent a fundamental species responsible for mediating A? toxicity in
AD (2, 16).
Given the critical role that A? oligomers appear to play in the patho-
of AD. We used the 3xTg-AD mice, which develop an age-dependent
accumulation of both plaques and tangles in AD-relevant brain regions
oligomers, and fibrils formation. Of particular relevance, we found that
oligomerization of A? appears to commence intraneuronally in the
3xTg-AD brains, a finding consistent with other in vitro and in vivo
studies (26–28). As we previously showed that the administration of
forms of tau pathology (6), here we extended these studies and showed
that the administration of an A? oligomeric-specific antibody is also
able to reduce the tau pathology in these mice. These findings suggest
MATERIALS AND METHODS
(25). Briefly, the 3xTg-AD mice were derived by co-microinjecting two
independent transgenes encoding human APPSweand the human
tauP301L(both under control of the mouse Thy1.2-regulatory element)
into single-cell embryos harvested from homozygous mutant PS1M146V
knock-in (PS1-KI) mice.
Immunoblotting—Brains from 3xTg-AD and NonTg mice were
homogenized in 2% SDS supplemented with a complete miniprotease
inhibitor tablet (Roche Diagnostics). The homogenized mixes were
* This work was supported by Grant AG0212982 from the NIA, National Institutes of
Health (to F. M. L.), Grants AG 18877, AG 22547, and AG 11385 from the National
Institutes of Health (to W. L. K.), and Grant AG00538 from the Larry L. Hillblom Foun-
dation and National Institutes of Health (to C. G. G.). The costs of publication of this
fore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
1To whom correspondence should be addressed: Dept. of Neurobiology and Behavior,
University of California, Irvine, 1109 Gillespie Neuroscience Bldg. Irvine, CA 92697-
4545. Tel.: 949-824-1232; Fax: 949-824-7356; E-mail: email@example.com.
2The abbreviations used are: AD, Alzheimer disease; A?, amyloid-?; LTP, long term
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 281, NO. 3, pp. 1599–1604, January 20, 2006
© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.Printed in the U.S.A.
JANUARY 20, 2006•VOLUME 281•NUMBER 3JOURNAL OF BIOLOGICAL CHEMISTRY 1599
by guest on November 6, 2015
William L. Klein and Frank M. LaFerla
2006, 281:1599-1604.J. Biol. Chem.
Tran, Mary P. Lambert, Charles G. Glabe,
Salvatore Oddo, Antonella Caccamo, Levina
AND TAU PATHOLOGY
Alzheimer Disease: A LINK BETWEEN A
Oligomerization in an
Temporal Profile of Amyloid-
Protein Structure and Folding:
doi: 10.1074/jbc.M507892200 originally published online November 10, 2005
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