invasive nanotechnology-assisted approach for
optical control of in vitro and in vivo neuronal
activity. We show spectral tuning of UCNPs for
compatibility with the current toolbox of light-activated channels (9) that is sufficient for functional activation and inhibition across a variety of
deep brain structures. Future characterization of
the interaction of UCNPs with neural tissue will
allow for better biocompatibility and long-term
utility. In parallel, systematic optimization of the
dose of UCNP injection and the parameters of
NIR stimulation will provide improved accuracy
and safety. Such data might also present an upper
limit to the adaptability and efficiency of NIR
stimulation. Furthermore, refinements of the
nanoparticles to establish precise cell-type or
intracellular targeting (17, 18), as well as improved
delivery methods that would further reduce
invasiveness (35), will advance the utility of the
approach. These methods, combined with the
enhanced ability to express light-sensitive channels in the brain, may allow UCNP-mediated
neuronal control to complement or extend current approaches to deep brain stimulation and
neurological disorder therapies.
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We thank S. Wada and T. Tsukihana (RIKEN Center for Advanced
Photonics) for technical advice and assistance with laser optics;
H. Hirase [RIKEN Brain Science Institute (BSI)] for helpful
discussion on in vivo toxicity assay and gifts of antibodies against
GFAP (glial fibrillary acidic protein) and Iba1; S. Itohara (RIKEN
BSI) for the gift of antibody against Caspase-3; T. Launey (RIKEN
BSI) for helpful discussion on electron microscopy; and
C. Yokoyama (RIKEN BSI) and F. Xu (University of Science and
Technology of China) for comments on the manuscript. This work
was supported by JSPS (Japan Society for the Promotion of
Science) Postdoctoral Fellowship (16F16386) (S.C.); RIKEN Special
Postdoctoral Researchers Program (S.C.); RIKEN BSI (T.J.M.);
Grant-in-Aid for Scientific Research on Innovative Areas from MEXT
(the Ministry of Education, Culture, Sports, Science and Technology
of Japan) (17H05591) (T.J.M.); Grant-in-Aid for Young Scientists B
(16K18373) (S.C.); the Singapore Ministry of Education (grant
R143000627112, R143000642112) (X.L.); the National Research
Foundation of Singapore under its Competitive Research Programme
(CRP Award no. NRF-CRP15-2015-03) (X.L.); Grants-in-Aid for
Scientific Research (25000015) (M.K.); Grants-in-Aid for Scientific
Research (17H01387 and 25117006) (S.O.); and Core Research for
Evolutional Science and Technology from the Japanese Science
and Technology Agency (JPMJCR14W2) (S.O.). All data necessary
to assess the conclusions of this research are available in the
text and supplementary materials. Data related to the synthesis
and characterization of UCNPs are available via the X.L. laboratory
website ( http://liuxg.science.nus.edu.sg). Data related to the
application of UCNP-mediated optogenetics in the mouse brain are
archived on the servers of Laboratory for Circuit and Behavioral
Physiology at the RIKEN Brain Science Institute and accessible at
http://cbp.brain.riken.jp/chen_et_al. All materials are available
Materials and Methods
Figs. S1 to S18
Tables S1 and S2
3 October 2017; accepted 7 December 2017
Defective cholesterol clearance limits
remyelination in the aged central
Ludovico Cantuti-Castelvetri,1,2,3,4 Dirk Fitzner,1,5 Mar Bosch-Queralt,1,2,3,4
Marie-Theres Weil,1,6 Minhui Su,1,2,3,4 Paromita Sen,1 Torben Ruhwedel,7
Miso Mitkovski,8 George Trendelenburg,5 Dieter Lütjohann,9
Wiebke Möbius,6,7 Mikael Simons1,2,3,4†
Age-associated decline in regeneration capacity limits the restoration of nervous system
functionality after injury. In a model for demyelination, we found that old mice fail to
resolve the inflammatory response initiated after myelin damage. Aged phagocytes
accumulated excessive amounts of myelin debris, which triggered cholesterol crystal
formation and phagolysosomal membrane rupture and stimulated inflammasomes.
Myelin debris clearance required cholesterol transporters, including apolipoprotein
E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity
of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can
overwhelm the efflux capacity of phagocytes, resulting in a phase transition of
cholesterol into crystals and thereby inducing a maladaptive immune response that
impedes tissue regeneration.
Remyelination restores rapid transmission of nerve impulses and axonal function in the central nervous system (CNS) of pa- tients with demyelinating diseases such as multiple sclerosis (MS). Although remyelination can occur in MS, age-associated decline in
myelin repair contributes to chronic progressive
disease and disability (1). Thus, understanding
the cause of and preventing this decline are key
goals in regenerative medicine (2–4). So far, epigenetic changes within aging oligodendrocyte
progenitor cells and declines in phagocytic capacity of aged blood-derived monocytes have
been identified as possible mechanisms (5, 6).
We implemented a toxin-induced model, in which
a single injection of lysolecithin (lysophosphati-
dylcholine) induces a focal demyelinating lesion
in the white matter of the brain or spinal cord of
mice. In lesioned animals, demyelination is com-
plete within 4 days, followed by a repair process
684 9 FEBRUARY 2018 • VOL 359 ISSUE 6376 sciencemag.org SCIENCE
1Max Planck Institute of Experimental Medicine, 37075
Göttingen, Germany. 2Munich Cluster for Systems
Neurology (SyNergy), 81377 Munich, Germany. 3Institute
of Neuronal Cell Biology, Technical University Munich,
80805 Munich, Germany. 4German Center for
Neurodegenerative Disease (DZNE), 81377 Munich,
Germany. 5Department of Neurology, University of
Göttingen Medical Center, 37075 Göttingen, Germany.
6Center for Nanoscale Microscopy and Molecular
Physiology of the Brain (CNMPB), 37075 Göttingen,
Germany. 7Department of Neurogenetics, Max Planck
Institute of Experimental Medicine, 37075 Göttingen,
Germany. 8Light Microscopy Facility, Max Planck Institute
of Experimental Medicine, 37075 Göttingen Germany.
9Institute for Clinical Chemistry and Clinical
Pharmacology, University of Bonn, 53127 Bonn, Germany.
*These authors contributed equally to this work.
†Corresponding author. Email: email@example.com