KEY RESOURCES TABLE.

REAGENT or RESOURCE	SOURCE	IDENTIFIER

Antibodies

Mouse anti-AT8	Thermo Fisher Scientific	Cat#: MN1020; RRID: AB_223647
Rat anti-CD68	Bio-Rad	Cat#: MCA1957; RRID: AB_322219
Mouse anti-GAPDH	Cell Signaling	Cat#: 97166; RRID: AB_2756824
Mouse anti-GFAP	Millipore	Cat#: MAB3402; RRID: AB_94844
Rabbit anti-HMGB1	Abcam	Cat#: ab18256; RRID: AB_444360
Rabbit anti-Acetyl-HMGB1 (Lys29)	Thermo Fisher Scientific	Cat#: PA5–120416 RRID: AB_2913988
Rabbit anti-Iba1	Wako	Cat#: 019–19741; RRID: AB_839504
Rabbit anti-MBP	Abcam	Cat#: ab40390 RRID: AB_1141521
Goat anti-Iba1	Abcam	Cat#: ab5076 RRID: AB_2224402
Guinea Pig anti-NeuN	Millipore	Cat#: ABN90; RRID: AB_11205592
Mouse anti-SIRT1	Abcam	Cat#: ab110304 RRID: AB_10864359
Rabbit anti-S100β	Abcam	Cat#: ab52642; RRID: AB_882426
Rabbit anti-TUJ1	Biolegend	Cat#: 802001; RRID: AB_2564645
Donkey anti-mouse Biotin-SP	Jackson Immuno Research Labs	Cat#: 715-065-150; RRID: AB_2307438
Donkey anti-mouse Alexa Fluor 488	Abcam	Cat#: ab150105; RRID: AB_2732856
Donkey anti-rabbit Alexa Fluor 488	Abcam	Cat#: ab150073; RRID: AB_2636877
Donkey anti-rat Alexa Fluor 488	Abcam	Cat#: ab150153; RRID: AB_2737355
Donkey anti-mouse Alexa Fluor 594	Abcam	Cat#: ab150108 RRID: AB_2732073
Donkey anti-rabbit Alexa Fluor 594	Abcam	Cat#: ab150076 RRID: AB_2782993
Donkey anti-guinea pig 594	Jackson Immuno Research Labs	Cat#: 706-585-148; RRID: AB_2340474
Donkey anti-mouse 647	Abcam	Cat#: ab150107; RRID: AB_2890037
Donkey anti-rabbit 647	Abcam	Cat#ab150075; RRID: AB_2752244
Donkey anti-guinea pig 647	Jackson Immuno Research Labs	Cat#: 706–605-148; RRID: AB_2340476
Donkey anti-mouse IRDye 800CW	LI-COR	Cat#: 926–32212; RRID: AB_621847
Donkey anti-rabbit IRDye 680RD	LI-COR	Cat#: 926–68073; RRID: AB_10954442

Chemicals, peptides, and recombinant proteins

Artificial CSF	Harvard Apparatus	Cat#: 59-7316
Biotinylated donkey anti-mouse	Jackson Immuno Research Labs	Cat#: 715-065-150
Benzonase^® Nuclease	Sigma-Aldrich	Cat#: E1014
cOmplete Protease Inhibitor Cocktail	Roche	Cat#: 11836145001
DAPI	Thermofischer	Cat#: 62248
DPX mounting medium	Sigma-Aldrich	Cat#: 6522
Ethyl Pyruvate	Sigma-Aldrich	Cat#: 8066170500
Glycyrrhizic Acid	Sigma-Aldrich	Cat#: 50531–50G
Intercept Blocking Buffer (PBS)	LI-COR	Cat#: 927–70001
M.O.M. blocking buffer	Vector Labs	Cat#: MKB-2213–1
NewBlot IR Stripping Buffer	LICOR	Cat#: 928–40028
Normal Donkey Serum	Jackson Immuno Research Labs	Cat#: 17000121
NuPage 12% Bis-Tris gel	Invitrogen	Cat#: NP0343
NuPage MOPS SDS Running Buffer	Novex	Cat#: NP0001
Paraformaldehyde	Electron Microscopy Sciences	Cat#: 15710-S
ProLong Gold mounting medium	Vector Labs	Cat#: P36930
PhosSTOP phosphatase inhibitor	Roche	Cat#: 04–906-845–001
RAB buffer	G Biosciences	Cat#: 786–91
Recombinant Human HMGB1 protein	R&D Systems	Cat#: 1690-HMB-050
RIPA buffer	Thermo Fisher Scientific	Cat#: 89900
Saline (0.9%)	Fisher Scientific	Cat#: Z1376
Sudan Black B	Sigma-Aldrich	Cat#: 199664

Critical commercial assays

Avidin/Biotin blocking kit	Vector Labs	Cat#: SP-2001
ABC-HRP Kit, Peroxidase	Vector Labs	Cat#: PK-6100
DAB Substrate Kit	Vector Labs	Cat#: SK-4100
Chromium Next GEM Single Cell 3' Library and Gel Bead kit v3.1	10x Genomics	Cat#: 1000128
Mouse HMGB1 ELISA kit	Novus Biologicals	Cat#: NBP2–62767
V-PLEX Plus Mouse Cytokine 19-Plex kit	Meso Scal Diagnostics	Cat#: K15255G
NE-PER nuclear and cytoplasmic extraction reagents	Thermo Fisher Scientific	Cat#: 78835

Deposited data

Raw snRNA-seq data	This paper	GEO accession number: GSE242153
Processed snRNA-seq data	This paper	Tables S1, S2, S3, S4, S5, S6

Experimental models: Organisms/strains

Mouse: APOE3-KI: Apoetm2(APOE_i3)Yhg	Yadong Huang	Bien-Lyet. al.⁴⁹, 2012
Mouse: APOE4-KI: Apoetm3(APOE_i4)Yhg	Yadong Huang	Bien-Lyet. al.⁴⁹, 2012
Mouse; PS19-E4 APOE4-KI crossbred to Tau-P301S (PS19 line) (Jax #008169)	This paper	N/A
Mouse: PS19-E3 APOE3-KI crossbred to Tau-P301S (PS19 line) (Jax #008169)	This paper	N/A
Mouse: PS19-E4/Syn1-Cre APOE4-KI crossbred to Tau P301S (PS19 line; Jax #008169) crossbred to Syn1-Cre (Jax 003966)	This paper	N/A
Mouse: Wildtype	The Jackson Laboratory	Cat#: 000664
Human: Brain tissue from ROSMAP cohort	Bennett et al⁹³2018	radc.rush.edu

Oligonucleotides

Software and algorithms

GraphPad Prism 9 for Mac	GraphPad Software	https://www.graphpad.com/scientific-software/prism/
Fiji v2.3	Schindelin et al, 2012	https://imagej.net/software/fiji/downloads
Image Studio Lite v.5.2.5	LI-COR	https://www.licor.com/bio/image-studio-lite/resources
Seurat v4.0.5	Hao et al⁹⁴, 2021	https://satijalab.org/seurat/artides/install.html
Cellranger v6.1.1	10x Genomics	https://support.10xgenomics.com/single-cell-gene-expression/software/downloads/6.1/
glmGamPoi v1.6.0	Ahlmann-Eltze et al⁹⁵, 2021	https://bioconductor.org/packages/release/bioc/html/glmGamPoi.html
lme4 v.1.1–27.1	Bates etal⁹⁶, 2015	https://cran.r-project.org/web/packages/lme4/index.html
lme4 v.1.1–30	Bates etal⁹⁶, 2015	https://cran.r-project.org/web/packages/lme4/index.html
R v4.1.2	R Core Team	https://www.R-project.org
Codes generated in this study	This paper	https://github.com/ADNetworksPPG/YH_NK01_APOE4_HMGB1_paper/
Codes generated in this study	This paper	https://doi.org/10.5281/zenodo.8309839.

Other

Aperio VERSA slide scanning microscope	Leica	N/A
AtmosLM Collection Probe (1000 kDa)	Eicom	Cat#:PEP-4–01
Bone drill bit (1.2mm)	BASi	Cat#: MD-1360
Fraction Collector	BASi	Cat#: MD-1201
FV3000 confocal laser scanning microscope	Olympus	N/A
GC FujiCEM 2	GC America	Cat#: 441001
Microdialysis stand-alone system	BASi	Cat#: MD-1409
Nylon monofilament non-abaorbable 6–0 sutures	Henry Schein	Cat#: 5617265
Odyssey CLx Imaging System	LI-COR	N/A
Optima TLX Ultracentrifuge	Beckman Coulter	N/A
PEG-4 AtmosLM dummy probe	Amuza	Cat#: 600.134.00
PEG-4 AtmosLM guide cannula	Amuza	Cat#: 600.133.00
Polytron PT-MR 3100D homogenizer	Kinematica AG	Cat: #PF-768-0025-04-02
Spectrophotometer SpectraMax M5	Molecular Devices	N/A
Stereotaxic alignment system model 940	Kopf Instruments	N/A
Trans-blot turbo transfer system	BIO-RAD	Cat#: 1704150
Sector imager 2400	Meso Scale Diagnostics	N/A