Fig 7. hTDP-43 interacts with TREM2 in human tissues and in silico.

a, TREM2 immunoblots of frozen autopsied cortex and spinal cord specimens of ALS patients and age matched controls. b, Quantification of TREM2 level relative to GAPDH (n =12 for control, n = 16 for ALS patients). c, Endogenous TDP-43 of frozen autopsied spinal cord specimens from ALS patients was co-immunoprecipitated with TREM2. Experiments were independently repeated three times. d-g, Cartoon models of the human TREM2 extracellular ligand-binding domain in complex with four low-complexity domain (LCD) fragments of TDP-43, including NGF, AMM, SWG and GFN (NFG: N³¹²FGAFS³¹⁷; AMM: A³²¹MMAAA³²⁶; SWG: S³³³WGMMGMLASQ³⁴³; GFN: G³⁹⁶FNGGFG⁴⁰²). h, Surface models of the TREM2 complex showing overlapping binding sites of GFN and NFG and distinct binding sites of NFG, AMM, and SWG. i, Surface plasmon resonance (SPR) analysis of the binding between recombinant hTREM2 ECD (Met1-Ser174) with full length hTDP-43. hTREM2 ECD was immobilized on a CM5 BIAcore chip and interacted with full length hTDP-43 at the indicated concentrations. j, SPR analysis of the binding between recombinant hTREM2 ECD (Met1-Ser174) with SWG and GFN at the indicated concentrations. SPR was independently repeated three times for full length hTDP-43. In b, Significance was calculated using two-tailed unpaired Student’s t-test. Data represented as mean ± SEM. n.s., not significant, *P < 0.05, **P < 0.01, *** P < 0.001. Cortex: P = 0.0316, t = 2.271, d.f. =26; SC: P = 0.0045, t = 3.112, d.f. = 26.