1212-C 3 DECEMBER 2021 • VOL 374 ISSUE 6572 science.org SCIENCE
RESEARCH
ALZHEIMER’S DISEASE
Inhibiting AKTivity
Triggering receptor expressed on
myeloid cells 2 (TREM2) has been
implicated in the pathophysiology
of Alzheimer’s disease (AD), and
the R47H variant of the TREM2
gene is associated with increased
risk of late-onset AD. Sayed et al.
studied the mechanisms respon-
sible for the detrimental effects of
the variant. R47H-TREM2 results
in increased expression of inflam-
matory molecules and enhanced
AKT signaling in microglia from
patients. The results were rep-
licated in vivo using a knock-in
mouse model. Moreover, the
mutation worsened AD-like
pathology and cognitive deficits
in a model of tauopathy. Inhibiting
AKT signaling had therapeutic
effects in mice, suggesting that
targeting AKT might be effective
in patients with AD carrying the
R47H mutation. —MM
Sci. Transl. Med. 13 , eabe3947 (2021).
PSORIASIS
Amplification of skin
inflammation
The proteins BCL10 and MALT1
form ubiquitously expressed sig-
nalosomes that control immune
and inflammatory pathways in
many tissues. Pathological inter-
play between the immune system
and keratinocytes is known to
drive pathogenesis in psoriasis;
however, the molecular and cellu-
lar functions of BCL10 and MALT1
in the complex pathogenesis of
psoriasis are not well defined.
Kurgyis et al. engineered mouse
models to activate, inactivate, or
attenuate BCL10/MALT1 signaling
specifically in keratinocytes. They
found that these proteins function
to initiate and amplify keratino-
cyte responses to inflammatory
cytokines and that their constitu-
tive activation is sufficient to drive
psoriasis. Furthermore, BCL10/
MALT1 signaling is frequently
altered in human psoriasis
patients, suggesting that targeting
the BCL10/MALT1 signalosome
using MALT1 inhibitors may be a
promising therapeutic approach
for treating psoriasis. —HMI
Sci. Immunol. 6 , eabi4425 (2021).