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DAMed in (Trem) 2 Steps

Sandro Da Mesquita1 and Jonathan Kipnis1,*
1Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville,

VA 22908, USA
*Correspondence: [email protected]
http://dx.doi.org/10.1016/j.cell.2017.05.039

The role of microglia in neurodegenerative diseases has been controversial. In this issue, Keren-
Shaul et al. identify a unique population of disease-associated microglia (DAM) that develop in
two steps and may help to restrict damage in Alzheimer and related diseases.

In the early 1920s, Pio del Rio Hortega 2012), and other neurodegenerative dis- single-cell genomics to better understand
identified microglia and their phenotypes eases is still under debate, in part because which microglial subtypes are associated
in different pathologies. Thereafter, prog- of how heterogeneous these populations with AD and other pathologies. In their un-
ress in understanding of microglial devel- could be. To begin to understand the di- biased analysis of thousands of cells, they
opment and function was gradual until a versity of immune cells in the brain and happen upon two unique microglial popu-
seminal study identified primordial macro- how they may affect diseases, Keren- lations found in the brain cortex of AD
phages as precursors of microglia, whose Shaul et al. (Keren-Shaul et al., 2017) in mice, but not in healthy mice (wild-type
arrival in the central nervous system coin- this issue of Cell use single-cell tran- or AD mice in an early phase of disease)
cides with development of the blood scriptomics, to comprehensively map all or in brain areas less affected by amyloid
vasculature (Ginhoux et al., 2010). Subse- immune populations in the brains and pathology. They call these cells disease-
quent studies confirmed that under phys- meninges of normal mice and animal associated microglia (DAM).
iological conditions peripheral monocytes models of Alzheimer’s-like pathology. The role of the Trem2 protein, one of the
do not engraft the brain parenchyma, but One of the problems with previous major risk factors for AD, much as the role
rather that throughout life the microglial studies is that isolation of microglia has of microglia in animal AD models, has
pool is maintained by self-proliferation been based on only two markers, CD45 also been hotly debated (Ulrich et al.,
(Goldmann et al., 2013). After CNS injury and CD11b. Whereas meaningful data 2017). Keren-Shaul et al. new data show
or neuroinflammation (as in experimental can be obtained from microglia isolated that as disease progresses, microglia
autoimmune encephalomyelitis), periph- from normal brains, the characteristic het- evolve into DAM in a two-step process. In
eral monocytes invade the parenchyma erogeneity of microglia in diseased brains the first step, which is Trem2-independent,
but do not persist there. The role of micro- precludes accurate isolation of their sub- the homeostatic microglial signature is lost,
glia versus engrafted peripheral mono- types based on so few markers, since and in the second, Trem2-dependent step,
cytes in Alzheimer’s disease (AD) (Bois- possible microglial subpopulations asso- the cells acquire a phenotype associated
sonneault et al., 2009), amyotrophic ciated with a particular pathology would with phagocytosis and lipid metabolism
lateral sclerosis (ALS) (Butovsky et al., be missed. This is exactly what the cur- (Figure 1). It remains to be tested whether
2012), Rett syndrome (Derecki et al., rent Cell paper shows. The authors exploit DAM depletion affects disease initiation

1172 Cell 169, June 15, 2017 ª 2017 Elsevier Inc.

Figure 1. A Two-Step Process Promotes the Transition from Homeostatic to Disease-Associated Microglia
Keren-Shaul et al. characterize a new type of microglia, DAM, found in the brains of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and aged mice.
To become DAM, microglia undergo an initial Trem2-independent step of activation, followed by a second step that is Trem2-dependent. Although the molecular
mediators of this DAM programing steps remain elusive, the authors show that these cells start by losing their homeostatic gene signature and end up by
upregulating genes involved in lipid metabolism and phagocytosis, which allows them to acquire a protective phenotype in the context of neurodegeneration.

and/or progression in AD and ALS models. and meninges, which harbor monocytes 2013). Thus, although these studies
It would also be interesting to test if (among other peripheral immune cells). showed quantitatively similar microglial
inducing the DAM phenotype in healthy Therefore, the changes observed here in depletion, their behavioral outcomes
young mice or even in developing mice myeloid cells, other than microglia, with were opposite. These and other discrep-
produces changes in behavior and cogni- disease progression are not necessarily ancies may be attributable to different mi-
tive function. The authors also state that parenchymal, but may be meningeal or a crobiota to which the mice are exposed.
the mechanism for sensing the environ- combination of both. Future studies should Microglia are brain-resident immune cells
ment and activating microglia is not under- aim at deciphering the distinctive pheno- that constantly change in response to their
stood, and the molecular trigger that acti- types of parenchymal immune cells in environment, which includes the well-
vates microglia is unknown. Presumably order to determine whether peripheral cells established gut brain axis (Erny et al.,
such a trigger is common to neurodegener- engraft the parenchyma, and if so, how this 2015). Therefore, single-cell sequencing
ative diseases like AD and ALS and present affects their phenotype and function. of brain pathology-associated microglia
in aged brains. The immediate suspects for Another recently explored, yet still in mice housed under different conditions
environmental sensing would be Toll-like contradictory, aspect of microglial biology (germ-free versus specific-pathogen free)
and NOD-like receptors. Thus, a plausible is their homeostatic function. Pharma- may reveal different microglia phenotypes
future target for neuroprotective therapies cological treatment of microglia using between different laboratories and thus
might be the identification of molecular M-CSF receptor antagonists results in explain some discrepancies.
cues that trigger the DAM phenotype. their almost complete depletion but with Microglia have long been the Cinderella
The role of peripherally engrafting mono- no cognitive deficits (Elmore et al., 2014). of the CNS, but there is hope that novel
cytes is not addressed directly in the Microglial depletion using alternative tools emerging in the recent years, such
current study (Keren-Shaul et al., 2017) (genetic) method does yield cognitive as these used in the current study, will
because the cells were isolated from the deficits, supposedly owing to lack of serve as the magic wand that confers on
entire brain, including the choroid plexus microglia-derived BDNF (Parkhurst et al., these cells their rightful elevated status.

Cell 169, June 15, 2017 1173

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Elmore, M.R., Najafi, A.R., Koike, M.A., Dagher, Goldmann, T., Wieghofer, P., Müller, P.F., Wolf, Y., Ulrich, J.D., Ulland, T.K., Colonna, M., and Holtz-
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Sex at Atomic Resolution

Jae Yeon Hwang1 and Jean-Ju Chung1,2,*
1Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA
2Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA
*Correspondence: [email protected]
http://dx.doi.org/10.1016/j.cell.2017.05.043

Interspecies fertilization is rare, partly due to species separation enforced at the molecular
level. In this issue, Raj et al. now reveal the crystal structures of mollusk egg coat protein,
VERL, complexed with cognate sperm protein lysin. Given that VERL is structurally similar to
mammalian ZP2, the mechanism elucidating species-specific gamete recognition likely exists
in mammals.

To sexually reproduce, life must solve sperm proteins in abalone and mam- the first atomic-resolution structures of
one of many fundamental problems: the mals, respectively. Abalone sperm lysin, domain repeats of VERL, separately
egg must allow a foreign cell, a sperm, which is named after its VE dissolving ac- and in complex with lysin. The study de-
to penetrate its thick egg coat. The free- tivity, was identified as a 16-kDa protein scribes the molecular and structural ba-
spawning marine mollusks, abalones, released from the acrosome (Lewis sis of species-specific sperm-egg coat
overlap breeding seasons and habitats et al., 1982), an organelle at the tip of recognition. Interestingly, VERL repeats
yet fertilize species specifically. How is the sperm head. Lysin creates a hole in are structurally similar to a functional
this species-specific gamete recognition the egg VE in a non-enzymatic, species- domain of mammalian ZP2, despite their
achieved? selective manner (Vacquier et al., 1990). sequence divergence and evolutionary
An abalone egg is coated with a VERL was identified as the VE receptor distance.
heavily glycosylated, outer protective for lysin, with the surprisingly large mo- VERL is a rod-like tandem array of 22
layer called the vitelline envelope (VE), lecular weight of 2 MDa (Swanson and VERL repeats (VR1–VR22), with a poly-
which is analogous to the zona pellucida Vacquier, 1997). merization module that is conserved in
(ZP) in mammals. Sperm must penetrate Although lysin’s crystal structure has all egg coat proteins, the C-terminal ZP
these egg coats—the main block against been determined (Shaw et al., 1993), domain (Galindo et al., 2002). VR1 and
cross-species fertilization—to reach the the structural details of VERL and its VR2 are highly variable in sequences,
egg plasma membrane. The initial interaction with lysin have been un- whereas VR3–VR22 have almost iden-
sperm-egg recognition was conceptual- known. The highly glycosylated VERL tical sequences. The investigators clev-
ized as lock-and-key, species-specific has been resistant to crystallographic erly noticed that the N terminus of
binding between sperm proteins and re- determination, limiting our understanding VERL is under high evolutionary pres-
ceptors on the egg (Lillie, 1914). The VE of the mechanism by which VERL and sure, similar to mammalian ZP2, the
receptor for lysin (VERL) and ZP2 are lysin interact to disrupt the egg VE. In molecular component responsible for
the egg coat proteins that recognize this issue of Cell, Raj et al. (2017) present sperm recognition in the mammalian

1174 Cell 169, June 15, 2017 ª 2017 Elsevier Inc.