REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies
Anti-SHIP-1 Antibody (P1C1)	Santa Cruz Biotechnology	Cat# Sc-8425
	Santa Cruz Biotechnology	Cat# Sc-13119
Anti-β-Actin Antibody (C4)	Santa Cruz Biotechnology	Cat# Sc-47778
m-IgGκ BP-HRP	Santa Cruz Biotechnology	Cat# Sc-516102
TruStain FcX (anti-mouse CD16/32, Clone 93)	Biolegend	Cat# 101320
SHIP1-PE (Clone P1C1)	Biolegend	Cat # 656604
APC/Cyanine7 anti-mouse CD45 Antibody	Biolegend	Cat# 103116
CD45-PerCP (Clone 30-F11)	Biolegend	Cat# 557235
CD11b-APC_Cyanine7 (Clone M1/70)	BD Biosciences	Cat# 557657
iNOS-PE_eFlour610 (CloneCxNFT)	ThermoFisher Scientific	Cat #61-5920-80
Anti-PtdIns(3,4)P2	Echelon Biosciences	Cat# Z-P034
Phalloidin CruzFluor, 647 Conjugate	Santa Cruz Biotechnology	Cat#sc-363797
Alexa Fluor Plus 555 Goat anti-Mouse IgG (H+L)	Thermofisher Scientific	Cat# A32727
Bacterial and virus strains
DH 5 alpha competent E.coli	New England Biolabs	Cat# C2987H
BL2I (DE3) competent E.coli	New England Biolabs	Cat# C2527H
Chemicals, peptides, and recombinant proteins
beta-Amyloid Peptide (1-42) Human	Abcam	Cat#ab120301
Lipopolysaccharides from, E coli 0111:B4 (LPS)	Sigma-Aldrich	Cat# L2630
Beta-Amyloid (1-42), HiLyte™ Fluor 488-labeled Human	Anaspec	Cat# AS-60479-01
SHIP2 Lipid Phosphatase Enzyme	Echelon Biosciences	Cat # E-1000-2
BugBuster HT	Millipore	Cat# 70922-4
PI(3,4,5)P3 diC8 (PIP3)	Echelon Biosciences	Cat# P-3908-3
Malachite Green Solution	Echelon Biosciences	Cat# K-1501
eBioscience IC Fixation Buffer	ThermoFisher Scientific	Cat# 00-8222-49
eBioscience Permeabilization Buffer (10X)	ThermoFisher Scientific	Cat# 00-8333-56
Zombie Aqua Fixable Viability Kit	Biolegend	Cat #423102
Molecular Probes DAPI (4',6 Diamidino 2 Phenylindole, Dihydrochloride)	Thermo Fisher Scientific	Cat#D1306
Propidium iodide (PI)	Sigma	Cat#P4170
Mowiol (Polyvinyl Alcohol)	Sigma Merck	Cat#81381
Critical commercial assays
Plasmid Midi Kit (25)	Qiagen	Cat#12143
5’PtdIns(3,4,5)P3 Phophatase Activity Fluorescence Polarization Assay	Echelon Biosciences	Cat# K-1400
SuperSignal™ West Femto Maximum Sensitivity Substrate	Thermo Scientific™	Cat#34095
SuperSignal™ West Pico PLUS Chemiluminescent Substrate	Thermo Scientific™	Cat#34080
Halt™ Protease and Phosphatase Inhibitor Cocktail (100X)	Thermo Scientific™	Cat#78440
Syn PER Synaptic Protein Extraction Reagent	Thermo Fisher Scientific	Cat#87793
4–15% Mini-PROTEAN® TGX™ Precast Protein Gels	Bio-Rad	Cat#4561084
ELISA MAX™ Standard Set Mouse IL-6	BioLegend	Cat#431301
ELISA MAX™ Standard Set Mouse TNF-α	BioLegend	Cat#430901
TMB Substrate Set	BioLegend	Cat#421101
Cell Counting KIT-8 CCK-8	Dojindo Molecular Technologies Inc	Cat#CK04-20
Lipofectamine™ CRISPRMAX™ Cas9 Transfection Reagent	Thermo Fisher Scientific	Cat#CMAX00008
Truecut™ Cas9 Protein v2	Thermo Fisher Scientific	Cat#A36498
TrueGuide™ Synthetic sgRNA – Inpp5d mouse	Thermo Fisher Scientific	Cat#CRISPR494808_SGM
TrueGuide™ Synthetic sgRNA – Negative control	Thermo Fisher Scientific	Cat#A35526
Syn PER Synaptic Protein Extraction Reagent	Thermo Fisher Scientific	Cat#87793
V-PLEX Aβ Peptide Panel 1 (6E10) Kit	Meso Scale Discovery	Cat#K15200E-2
In Vitro Toxicology Assay Kit, Resazurin based	Sigma-Aldrich	Cat#TOX8-1KT
Phrodo™ iFL Green STP Ester (amine-reactive)	Thermo Fisher Scientific	Cat# P36012
Deposited data
SHIP2 structure	(Mills et al., 2012)	PDBID: 4A9C
SHIP2 structure	(Le Coq et al., 2017)	PDBID: 5OKM
INPP5B structure	(Tresaugues et al., 2014)	PDBID: 3MTC
Mcule library	(Hsieh et al., 2019)	N/A
Experimental models: Cell lines
BV2	ATCC	Cat# CRL-2467
Mouse BV2 scramble clone	Generated by Paolicelli’s lab	NA
Mouse BV2 Inpp5d clone 1	Generated by Paolicelli’s lab	NA
Mouse BV2 Inpp5d clone 2	Generated by Paolicelli’s lab	NA
Mouse BV2 cell-line	Kind gift of Marc Suter (UNIL)	CVCL_0182
Human Stably expressing-APPsw Hela cells	Kind gift from Lawrence Rajendran (UZH)	N/A
L929 mouse fibroblast cells	Kind gift of Steven Taffet (UPSTATE)	N/A
Experimental models: Organisms/strains
C57BL/6J	Jackson Laboratory	Cat#000664
B6.129S6-Inpp5dtm1Wgk/J	Jackson Laboratory	Cat#028255
B6.129P2-Lyz2tm1(cre)Ifo/J	Jackson Laboratory	Cat#004781
Mouse: B6.Cg-Tg(Camk2a-cre)T29-1Stl/J	Jackson Laboratory	Cat#005359
Mouse: B6.Cg-Gt(ROSA)26Sortm14(CAG tdTomato)Hze/J	Jackson Laboratory	Cat#007914
Oligonucleotides
See Table S2 for: SHIP1 cloning primers (pS97splitRBP_S1-Enz)	This Paper	N/A
See Table S2 for: SHIP1deltaC2 cloning primers (pS97splitRBP_ S1ΔC2)	This Paper	N/A
See Table S2 for: SHIP2 cloning primers (pS97splitRBP_ S2-Enz)	This Paper	N/A
Recombinant DNA
pET24TEV-tSHIP1	(Brooks et al., 2015)	Addgene ID 183770
pET24TEV-tSHIP2	(Russo et al., 2015)	Addgene ID 183771
pS97splitRBP	(Ha et al., 2019)	N/A
pS97splitRBP_S1ΔC2	This paper	Addgene ID 183769
pS97splitRBP_S1-Enz	This paper	Addgene ID 183767
pS97splitRBP_S2-Enz	This paper	Addgene ID 183768
Software and algorithms
AtomNet® AI technology	This paper	N/A
FlowJo v10.8.1	BD Biosciences	https://www.flowjo.com
SpectroFlo Version 2.2.0.2	Cytek	https://cytekbio.com/pages/aurora
ImageJ	(Schneider et al., 2012)	https://imagej.nih.gov/ij/
Imaris	Bitplane	http://www.bitplane.com/imaris/imaris
Prism 9.2	GraphPad	https://www.graphpad.com/
BioTek Gen2 Data analysis software	Agilent	https://www.biotek.com/
Image Lab Software	Bio-rad	Cat# 12012931
Thunder Imaging System	Leica Microsystems	https://www.leica-microsystems.com
Other
HisTrap™ High Performance 5mL column	Cytiva Life Sciences	Cat# GE17-5248-01
Pierce Protein Concentrators 30KMWCO PES	Thermo Fisher Scientific	Cat#88529
DMEM/Ham's F-12 50/50 Mix [+] L-glutamine	Corning®	Cat#10-090-CV
Cellstripper™, Liquid	Corning®	Cat# 25-056-CI
Gibco™ DMEM, low glucose, pyruvate	ThermoFisher Scientific	Cat# 31885049
Trypsin-EDTA (0.05%), phenol red	ThermoFisher Scientific	Cat# 25300062
Poly-D-lysine Hydrobromide	Sigma Merck	Cat# P7886
μ-Slide 18 Well	IBI	Cat# 81817
Geneticin disulphate (G418)	Carl Roth	Cat# 108321-42-2
Zeocin™ Selection Reagent	ThermoFisher Scientific	Cat# R25001
Microvette® 100 Serum, 300 μL	Sarstedt	Cat#20.1308.100