Prion-Like Behavior of Amyloid-β

Jungsu Kim, et al.

Science 330, 918 (2010);
DOI: 10.1126/science.1198314

This copy is for your personal, non-commercial use only.

If you wish to distribute this article to others, you can order high-quality copies for your
colleagues, clients, or customers by clicking here.
Permission to republish or repurpose articles or portions of articles can be obtained by
following the guidelines here.

The following resources related to this article are available online at

www.sciencemag.org (this infomation is current as of April 27, 2011 ):

Downloaded from www.sciencemag.org on April 27, 2011

Updated information and services, including high-resolution figures, can be found in the online
version of this article at:
http://www.sciencemag.org/content/330/6006/918.full.html
A list of selected additional articles on the Science Web sites related to this article can be
found at:
http://www.sciencemag.org/content/330/6006/918.full.html#related
This article cites 10 articles, 7 of which can be accessed free:
http://www.sciencemag.org/content/330/6006/918.full.html#ref-list-1
This article has been cited by 1 articles hosted by HighWire Press; see:
http://www.sciencemag.org/content/330/6006/918.full.html#related-urls
This article appears in the following subject collections:
Medicine, Diseases
http://www.sciencemag.org/cgi/collection/medicine

Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the
American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright
2010 by the American Association for the Advancement of Science; all rights reserved. The title Science is a
registered trademark of AAAS.
 PERSPECTIVES
MEDICINE
Can Alzheimer’s disease arise through
Prion-Like Behavior of Amyloid- pathogenic transmission of a protein
aggregate?
Jungsu Kim and David M. Holtzman

C
an certain neurode-
generative diseases be
transmitted between
humans by an infectious agent?
The discovery that protein par-
ticles called prions can enter
healthy mammals, includ-
ing humans, and trigger a cas-
cade of endogenous protein
misfolding associated with
bovine spongiform encepha-
protein denaturation and specific immunode-
pletion of Aβ (6). Yet systemic administration
Amyloid of Aβ-containing brain lysates, either orally
or by intravenous, intraocular, or intranasal
injection, failed to induce cerebral Aβ amy-
loidosis in mice (7).
Brain extracts
with Aβ seeds Surprisingly, Eisele et al. show that intra-
peritoneal injection of mice with mouse brain
extracts containing Aβ aggregates leads to
Alzeimer’s disease earlier-onset amyloid deposition and other
mouse model pathological alterations in recipient mice (5

Downloaded from www.sciencemag.org on April 27, 2011

lopathy (“mad cow disease”) months after exposure) (see the figure). Aβ
and Creutzfeldt-Jakob dis- aggregates were predominantly associated
Transport by
ease, certainly demonstrates with cerebral blood vessels, and amyloidosis
monocytes?
this in prion diseases. Remark- was associated with local gliosis (prolifera-
ably, neuronal proteins such tion of glia in damaged areas) and hyperphos-
as tau, α-synuclein, and poly- Intraperitoneal phorylation of tau protein, the major compo-
glutamine aggregates, which injection nent of neurofibrillary tangles. Thus, cerebral
are causally implicated in the amyloidosis can be induced in a susceptible
neurodegenerative disorders host by Aβ-containing material delivered out-
Amyloid
Alzheimer’s disease, Parkin- side the brain. It is unclear why the previous
formation
son’s disease, and Huntington’s attempts with intravenous injection failed to
disease, respectively, can be trigger Aβ deposition. It is possible that other
released from donor cells and modes of administration could induce amy-
taken up by neighboring accep- loidosis if the incubation time of the injected
tor cells. Moreover, treatment seed is sufficiently long and if the seed has a
Recipient mouse
with exogenous misfolded proper conformation.
neuronal proteins, such as tau, The transmission mechanism by which the
can trigger the misfolding and peripherally injected amyloid-inducing fac-
aggregation of their properly Amyloid transmission. Injection of mouse brain extract containing tor penetrates into the brain is also not clear.
folded endogenous counter- Aβ seeds (similar to those found in the Alzheimer’s disease brain) The authors propose that macrophages and
parts in host cells and animals into the peritoneal cavity of mice (that are genetically engineered to monocytes in the peritoneal cavity could take
(1). Besides prions, there is yet develop amyloid plaques) accelerates Aβ deposition in the host brain. up Aβ-containing material, enter the general
no evidence that other neuro- The transport mechanism from peripheral tissue to the brain is unclear. circulation, migrate into the cerebral perivas-
degenerative diseases associ- cular space, and deliver seeds for amyloido-
ated with protein misfolding are transmissi- Aβ-containing amyloid plaques and tau- sis. Another possibility might be that some
ble between humans by an infectious agent. containing neurofibrillary tangles (3). Aβ Aβ-containing material gets rapidly into the
But on page 980 in this issue, Eisele et al. aggregation is characterized by a slow nucle- brain across the blood-brain barrier without
(2) report that peripherally injected (out- ation phase in which it undergoes a series of entering circulating cells.
side the brain) mouse brain lysates contain- association steps to form small seeds, and Still, Eisele et al. do not provide direct
ing aggregates of amyloid-β (Aβ)—the pep- a growth phase in which the seeds rapidly evidence that peripherally injected Aβ (inde-
tide that induces the formation of debilitating grow to form larger fibrils and ultimately, pendent of other Aβ-associated cofactors) in
brain plaques in Alzheimer’s disease—causes plaques (4). Plaque formation can be facili- the brain extracts is necessary and sufficient
plaque-associated pathological changes in tated by preformed seeds. Indeed, the forma- to trigger cerebral amyloid deposition. Induc-
the brains of recipient mice. This has impli- tion of amyloid plaques can be induced in tion of amyloid formation in vivo with syn-
cations for a pathogenic mechanism reminis- vivo by injecting brain extracts containing thetic Aβ has been unsuccessful so far, lead-
cent of prion transmission. such seeds (from patients with Alzheimer’s ing to the hypothesis that an amyloid-enhanc-
Alzheimer’s disease is characterized disease) into mice that are genetically engi- ing factor or a particular conformation of Aβ
CREDIT: Y. HAMMOND/SCIENCE

clinically by progressive cognitive decline, neered to be predisposed to developing brain aggregates is required to trigger Aβ deposi-
and pathologically by the formation of amyloidosis (5). This suggested that a factor tion in vivo (6). Similarly, numerous attempts
in the brain extract triggers amyloid forma- to trigger prion diseases with synthetic prion
tion in vivo, but it was not clear whether the proteins alone have not been successful (8).
Department of Neurology, Hope Center for Neurological
Disorders, Knight Alzheimer’s Disease Research Center,
factor is solely Aβ or whether other factors A recent study demonstrated the critical role
Washington University School of Medicine, St. Louis, MO are required. However, the amyloid-inducing of lipid molecules and RNAs as cofactors in
63110, USA. E-mail: holtzman@neuro.wustl.edu activity of brain extracts was abolished by producing recombinant infectious prions (9).

918 12 NOVEMBER 2010 VOL 330 SCIENCE www.sciencemag.org

Published by AAAS
 PERSPECTIVES

It is possible that cerebral Aβ amyloidosis also
requires brain-specific endogenous amyloid-
enhancing factors. Plaque-associated proteins
and lipids, such as apolipoprotein E, proteo-
glycan, and ganglioside, might serve as cofac-
tors and facilitate Aβ aggregation (10). The
chemical and physical features of the amy-
loid-inducing factor remain to be determined.
The cell-to-cell passage of misfolded
proteins opens up the possibility of new
treatment strategies for their associated
disorder, such as antibodies or small mole-
cules that block transmission of the protein.
However, such transmission imposes a cau-
tionary caveat for stem cell–based therapy.
Conveyance of misfolded protein into the
transplanted stem cells might limit thera-
peutic benefits.
References
1. B. Frost, M. I. Diamond, Nat. Rev. Neurosci. 11, 155
(2010).
2. Y. S. Eisele et al., Science 330, 980 (2010).
3. J. Hardy, D. J. Selkoe, Science 297, 353 (2002).
4. J. D. Harper, P. T. Lansbury Jr., Annu. Rev. Biochem. 66,
385 (1997).
5. M. D. Kane et al., J. Neurosci. 20, 3606 (2000).
6. M. Meyer-Luehmann et al., Science 313, 1781 (2006).
7. Y. S. Eisele et al., Proc. Natl. Acad. Sci. U.S.A. 106,
12926 (2009).
8. G. Legname et al., Science 305, 673 (2004).
9. F. Wang, X. Wang, C. G. Yuan, J. Ma, Science 327, 1132
(2010).
10. J. Kim, J. M. Basak, D. M. Holtzman, Neuron 63, 287
(2009).
10.1126/science.1198314

MATERIALS SCIENCE

Materials Ecology: Careful process design that considers material

use and reuse over the entire product life cycle
An Industrial Perspective

Downloaded from www.sciencemag.org on April 27, 2011

is important for a sustainable industry.

Paul Collier1 and Carina Maria Alles2

T
here are many reasons for the cur-
rent drive for more sustainable indus-
trial processes, including a desire
for enhanced societal value, lower-energy
demand, less waste, and more effective prod-
ucts. Much of this drive comes from a new
generation of industry CEOs who are com-
mitted to sustainability (1). Sustainability
naturally includes a view on what to do with
products at the end of their lives, and the best
modern products are designed to make recy-
cling easier. However, there is much that is
not deemed to be worth recycling and goes
into landfill (2). Population increase and
changes in consumption patterns combined
with the inefficient use of materials push us
toward a crisis point. To achieve stable long-
CREDIT: ADAPTED FROM WWW.EMERALDINSIGHT.COM/CONTENT_IMAGES/FIG10240170604001.PNG
rials ecology,” a less well known concept, was
examined at a recent Frontiers of Engineer-
ing event (5). Several of the ideas presented
below crystallized during the series of talks
and ensuing panel discussion. This term has
been used before, principally to describe met-
als and minerals (6); however, before our
modern age such philosophies were surpris-
ingly widespread (7).
Materials ecology is a subset of industrial
ecology and offers a materials-centered view
of manufacturing processes rather than a sys-
tems view. Materials ecology is about the
interconnectivity of materials and the rela-
tive cost of loop closure with respect to other
materials and the environment. Loop closure
refers to a process for converting a product at
the end of its life into a new material and is
related to the term “cradle to cradle” (8). By
necessity, it operates at smaller scales but is
intimately meshed with industrial ecology at
larger scales (see the figure).
In industrial ecology, a general approach
might be to examine a particular industrial
system—for example, for producing a refrig-
erator—and to test inputs and outputs (cover-
ing all raw materials, waste products, desired
products, pollutants, energy required, and
heat generated) against sustainability crite-
ria. For each new product, this is repeated,
recalculating inputs and outputs each time. A
materials ecology viewpoint would comple-
ment this approach by allowing us to make
connections between the same material used

term growth, something will in different processes.

have to change—and perhaps For example, polyeth-
a new approach based on the ylene terephthalate is
materials themselves can help. used in many prod-
Industrial ecology is now ucts, such as fibers
a thriving sector of engineer- and bottles. The mate-
ing design and practice and rials ecology approach
has become a welcome part of would focus on this
modern industrial life (3, 4). It individual material
derives from a high-level sys- and consider it as the
tems study of the energy and center of a network
material flows through industrial analysis diagram with
processes. The aim is to improve connections to all the
sustainability by closing loops products that can be
and recycling materials. “Mate- made from it. At each
link, all material and
1
Johnson Matthey Technology Centre,
Blount’s Court Road, Sonning Common,
energy inputs and out-
Reading, RG4 9NH, UK. 2DuPont Engi- puts are evaluated in
neering Research and Technology, DuPont terms of the closed-
Building D5085, 1007 Market Street, loop use of the mate-
Wilmington, DE 19898, USA. E-mail: col-
lipj@matthey.com, carina.alles@usa. rial (i.e., including
dupont.com In the loop. Schematic representation of manufacturing networks. recycles) and classi-

www.sciencemag.org SCIENCE VOL 330 12 NOVEMBER 2010 919

Published by AAAS