Science - 31 January 2020

INSIGHTS | PERSPECTIVES

sciencemag.org SCIENCE

PHOTO: CSERÉP

ET A

L. (

3 )

ary alkyl groups. Moreover, when they used
a propargylic bromide as the electrophilic
partner, the products were obtained in high
yields and with high selectivity for a single
orientation. The catalyst delivers one stereo-
isomer of the four possibilities (see the figure,
bottom). This type of doubly stereoconver-
gent cross-coupling has only been achieved
once before and only worked for the cyclic
pyrrolidine nucleophile described above ( 9 ).
The synthetic implications of this ap-
proach are exciting. In synthesis courses,
students are taught to “retrosynthetically”
disconnect target molecules into simpler
intermediates by “clearing” stereocenters
through bond disconnections ( 10 ). The op-
portunity to clear two stereocenters and dis-
connect the molecule into two much simpler
racemic starting materials is powerful. Al-
though this method requires the products to
have amide and alkyne groups, these are ripe
for elaboration and derivatization through
straightforward manipulations.
In addition, the limits of this strategy are
not yet defined. Deeper understanding of
the mechanism and the role of the amide
in coordinating the catalyst will help define
the other groups that can be used to orga-
nize the key catalytic intermediates and
transition states, along with the lengths of
the tether that are effective. Given the im-
portance of all-carbon quaternary stereo-
centers, there will be a demand to increase
the size limits of the alkyl groups and to
explore whether a single catalyst can cross-
couple tertiary alkylating agents to set vici-
nal stereocenters in which one or both are
quaternary ( 11 ). Last, a catalyst has been
discovered to deliver only one of the two
possible diastereomers. Given that each
diastereomer may elicit a different biologi-
cal response, it will be of interest to see if a
complementary catalyst can be discovered
to deliver the other diastereomer in equally
high enantiomeric excess and yield ( 12 ). j

REFERENCES AND NOTES

1. D. G. Brown, J. Boström, J. Med. Chem. 59 , 4443 (2016).


2. J. Choi, G. C. Fu, Science 356 , eaaf7230 (2017).


3. H. Huo, B. J. Gorsline, G. C. Fu, Science 367 , 559 (2020).


4. G. C. Fu, ACS Cent. Sci. 3 , 692 (2017).


5. S. L. Zultanski, G. C. Fu, J. Am. Chem. Soc. 135 , 624
   (2013).


6. C. Fischer, G. C. Fu, J. Am. Chem. Soc. 127 , 4594 (2005).
   7. A. H. Cherney, N. T. Kadunce, S. E. Reisman, Chem. Rev.
   115 , 9587 (2015).


7. C. J. Cordier, R. J. Lundgren, G. C. Fu, J. Am. Chem. Soc.
   135 , 10946 (2013).


8. X. Mu, Y. Shibata, Y. Makida, G. C. Fu, Angew. Chem. Int.
   Ed. 56 , 5821 (2017).


9. E. J. Corey, X.-M. Cheng, The Logic of Chemical Synthesis
   (Wiley, 1995).


10. Z. Wang, H. Yin, G. C. Fu, Nature 563 , 379 (2018).


11. S. Krautwald, E. M. Carreira, J. Am. Chem. Soc. 139 , 5627
    (2017).

ACKNOWLEDGMENTS
NIH (R35 GM131816) is gratefully acknowledged.

10.1126/science.aba4222

NEUROSCIENCE

Monitoring neuronal health

A multiscale imaging approach reveals a neuroimmune

communication pathway

By Axel Nimmerjahn

N

eurodegenerative disorders, most

commonly stroke, Alzheimer’s dis-

ease, and Parkinson’s disease, affect

millions of people worldwide ( 1 ).

Despite their different etiologies, a

frequent feature of neurodegenera-

tive disorders is the persistent activation

of the innate immune system ( 2 ). Control-

ling this inflammatory response in a way

that positively affects clinical outcomes

for cognition and behavior is a current

major challenge and requires deeper un-

derstanding of the cellular and molecular

mechanisms that govern neuroimmune

interactions. On page 528 of this issue,

Cserép et al. ( 3 ) identify a pathway through

which microglia, the innate immune sen-

sors of the central nervous system (CNS),

monitor and influence neuronal health.

Microglia are damage sensors for the

CNS. They continually surveil the paren-

chyma with highly motile processes and

rapidly respond to tissue disturbances.

However, the cellular and molecular mech-

anisms that control this structural and

functional plasticity remain incompletely

understood ( 4 , 5 ). Much attention has fo-

cused on the interaction between microglial

processes and neuronal synapses; this work

has uncovered their important roles in

activity-dependent synaptic plasticity and

synapse elimination in health and neuro-

degenerative disorders ( 6 ). However, much

less attention has focused on microglial

interactions with other cell compartments,

including the soma (cell body), where most

of a neuron’s function is controlled. Cserép

et al. show that targeted contact of microg-

lial processes with neuronal somas (see the

photo) is a prevalent feature of the mouse

and human brain, rooted in specialized ul-

trastructure, and provides neuroprotection

after injury. Inhibiting this protective re-

sponse results in increased cell loss.

The death of a sufficient number of neu-

rons can have devastating consequences for

quality of life, as is evident in patients liv-

ing with the effects of stroke, Parkinson’s

disease, or spinal cord injury. Furthermore,

given the limited regenerative capacity of the

CNS, neurons and their thousands of synap-

tic connections are typically not replaced

when these cells die prematurely ( 7 ). A key

role of immune sentinels such as microglia

is to protect neurons against intrinsic and

extrinsic threats, such as disruption of the

blood-brain barrier (which restricts extrava-

sation of blood-borne substances into the

brain) or viral infection. If the threat cannot

be eliminated or contained and a neuron

becomes critically injured or dysfunctional,

microglia face a difficult decision: Should re-

sources be directed toward rescuing this cell,

or should the cell be removed to prevent fur-

ther damage to neighboring and connected

neurons? To help guide this cell fate deci-

sion, microglia rely on a number of soluble

and membrane-bound signals ( 8 ).

One important messenger in this context

is adenosine triphosphate (ATP) and its

metabolites, including adenosine diphos-

phate (ADP). High extracellular concentra-

tions of ATP and ADP generated by injured

and stressed cells are detected by puriner-

gic receptors, including P2Y purinoceptor

12 (P2Y12 receptor), that are expressed on

microglia. Thus, high extracellular ATP

and ADP concentrations constitute a “find

me” signal that guides microglia to the site

of tissue damage. Lower concentrations of

ATP are generally released under physi-

ological conditions—for example, as a co-

neurotransmitter at synapses ( 4 , 5 ). The

study of Cserép et al. shows that the ac-

tivity-dependent release of ATP from ana-

tomical specializations on neuronal somas

Waitt Advanced Biophotonics Center, Salk Institute for

Biological Studies, La Jolla, CA 92037, USA.

Email: [email protected]

A microglial process (green) with P2Y purinoceptor

12 (black) contacts a neuron cell body (pink) in mouse.

510 31 JANUARY 2020 • VOL 367 ISSUE 6477

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