Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience
nature neuroscience
Article
https://doi.org/10.1038/s41593-023-01315-6
Tau activation of microglial cGAS–IFN
reduces MEF2C-mediated cognitive
resilience
Received: 17 May 2022
Accepted: 20 March 2023
Published online: xx xx xxxx
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Joe C. Udeochu1,8, Sadaf Amin 1,8 , Yige Huang 1,8, Li Fan 1,
Eileen Ruth S. Torres1, Gillian K. Carling 1, Bangyan Liu1, Hugo McGurran2,
Guillermo Coronas-Samano 1, Grant Kauwe3, Gergey Alzaem Mousa1,
Man Ying Wong1, Pearly Ye1, Ravi Kumar Nagiri 1, Iris Lo2, Julia Holtzman2,
Carlo Corona4, Allan Yarahmady5, Michael T. Gill2, Ravikiran M. Raju6,7,
Sue-Ann Mok 5, Shiaoching Gong1, Wenjie Luo 1, Mingrui Zhao1,
Tara E. Tracy 3, Rajiv R. Ratan4, Li-Huei Tsai 6, Subhash C. Sinha1 & Li Gan
1
Pathological hallmarks of Alzheimer’s disease (AD) precede clinical symptoms
by years, indicating a period of cognitive resilience before the onset of
dementia. Here, we report that activation of cyclic GMP–AMP synthase (cGAS)
diminishes cognitive resilience by decreasing the neuronal transcriptional
network of myocyte enhancer factor 2c (MEF2C) through type I interferon
(IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in
microglia, in part mediated by cytosolic leakage of mitochondrial DNA.
Genetic ablation of Cgas in mice with tauopathy diminished the microglial
IFN-I response, preserved synapse integrity and plasticity and protected
against cognitive impairment without affecting the pathogenic tau load. cGAS
ablation increased, while activation of IFN-I decreased, the neuronal MEF2C
expression network linked to cognitive resilience in AD. Pharmacological
inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C
transcriptional network and restored synaptic integrity, plasticity and
memory, supporting the therapeutic potential of targeting the cGAS–IFN–
MEF2C axis to improve resilience against AD-related pathological insults.
Alzheimer’s disease (AD) is the most common late-onset dementia.
A long preclinical asymptomatic period with increasing deposition of
amyloid-β plaques and tau aggregates transforms to a symptomatic
phase with cognitive decline1–3. While the transition is poorly understood, it coincides with alterations in innate immune responses, vasculature and metabolism3. Susceptibility to sporadic late-onset AD is
linked to single-nucleotide polymorphisms in innate immune genes4,5,
suggesting that maladaptive innate immune responses underlie the
cognitive decline.
Antiviral response pathways are upregulated in AD and regulate
microglial disease responses, including immune activation/suppression and synaptic pruning in aging and neurodegenerative diseases6–9.
Helen and Robert Appel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
The Gladstone Institute of Neurological Disease, San Francisco, CA, USA. 3Buck Institute for Research on Aging, Novato, CA, USA. 4Burke Neurological
Institute at Weill Cornell Medicine, White Plains, NY, USA. 5Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. 6The Picower
Institute of Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. 7Division
of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA. 8These authors contributed equally: Joe C. Udeochu, Sadaf Amin, Yige Huang.
e-mail: ;
1
2
Nature Neuroscience
Article
https://doi.org/10.1038/s41593-023-01315-6
a
b
Hallmark pathway
enrichment:
P301S versus Ntg
P301S versus Ntg
10.0
Irf7 Mx1
5.0
Irf9
Stat1
Ifi44
Ifit3
Stat2
0
–5
0
IFNγ response
IFNα response
Allograft rejection
Inflammatory response
TNF-α signaling via NF-κB
IL-6−JAK−STAT3 signaling
Complement
KRAS signaling up
Apoptosis
IL-2−STAT5 signaling
0
5
Increased
measurement
Predicted
activation
CGAS
STAT1
TNF
STAT3
STAT2
IRF9
IRF1
IRF7
NF-κB1
20
STTTCRNTTT IRF Q6
RYTTCCTG ETS2 B
ISRE 01
IRF Q6
ICSBP Q6
RGAGGAARY PU1 Q6
IRF7 01
IRF1 01
NFKAP PAB 01
NF-κB Q6
40
21/191
43/1,109
22/251
21/243
21/252
25/508
18/256
17/255
16/254
16/256
0
60
5
–log10 (FDR)
log2 (FC)
d
57/200
35/97
43/200
34/200
31/200
19/87
22/200
19/200
16/161
17/199
TF
enrichment:
P301S versus Ntg
f
e
Ntg
P301S
75 kDa
pTBK1
75 kDa
TBK1
37 kDa
GAPDH
pTBK1
1.5
**
1.0
0.5
0
Ntg
g
IFNβ1
IBA1
IFNαR
IFNα
STING
i
Merged
h
*
30
P301S
Percent area
Ntg
P301S
Ntg
*
20
10
0
IBA1
IBA1−STING overlap
Non-AD
P301S
AD
(Braak stage 0) (Braak stage 6)
75 kDa
pTBK1
37 kDa
GAPDH
j
pTBK1 relative values
(pTBK1/GAPDH)
IL-10
10
–log10 (FDR)
Relative values
(pTBK1/TBK1)
–log10 (FDR)
Cxcl10
c
50
**
40
30
20
10
0
Braak 0 Braak 6
Fig. 1 | The cGAS–STING pathway is activated in the hippocampi of mice
with tauopathy and in human AD brains. a, Volcano plot of RNA-seq data
from bulk hippocampal tissue from 8- to 9-month-old P301S transgenic and
non-transgenic mice (Wald test). Red and blue dots represent genes with a log2 FC
(fold change) of > 0.5 and < −0.5, respectively. All other genes are colored gray.
Selected upregulated IFN genes are labeled; n = 7 non-transgenic mice and n = 6
P301S transgenic mice; FDR, false discovery rate; Ntg, non-transgenic; FC, fold
change. b, Gene set enrichment analysis showing hallmark pathways associated
with the top 500 DEGs upregulated in P301S transgenic samples compared to
in non-transgenic samples. c, Gene set enrichment analysis showing the top
TFs associated with the top 500 DEGs upregulated in P301S transgenic samples
compared to in non-transgenic samples. d, IPA prediction of cGAS as an upstream
regulator of upregulated DEGs identified using an activation z score of >1 and
a P value overlap of <0.05. e, Western blots for pTBK1, total TBK1 and GAPDH
using hippocampal tissue lysates. Lanes 1–7: Ntg. Lanes 8–14: P301S transgenic.
f, Ratio of pTBK1 to TBK1 from e showing significantly higher pTBK1 in P301S
transgenic hippocampi than in non-transgenic hippocampi. Data are reported as
mean ± s.e.m.; n = 7 animals per genotype; **P = 0.0015 two-tailed unpaired t-test.
g, Representative immunofluorescence images of non-transgenic and P301S
trasgenic hippocampi labeled with anti-IBA1 (green) and anti-STING (red); scale
bar, 50 µm. h, Quantification of IBA1 and STING immunofluorescence intensities,
showing increased IBA1 coverage and IBA1–STING overlap in P301S transgenic
hippocampi. Results are presented as average intensity measurements from
three to four sections per animal. Data are reported as mean ± s.e.m.; Ntg,
n = 5; P301S, n = 5. IBA1: *P = 0.0498; IBA1–STING overlap: *P = 0.0497. Data
were analyzed by two-tailed unpaired t-test. i, Representative western blots for
pTBK1 and GAPDH using human frontal cortex brain lysates. Lanes 1–3: non-AD
(Braak stage 0). Lanes 4–6: AD (Braak stage 6). j, Ratio of pTBK1 to GAPDH from i
showing significantly higher pTBK1 in AD brains than in non-AD brains. Data are
reported as (...truncated)
