Neuron-derived Thioredoxin-80: a novel regulator of type-I interferon response in microglia

Oxidative stress and neuroinflammation play a central role in Alzheimer’s Disease (AD) pathogenesis. However, the mechanism by which these processes lead to neurodegeneration is still not fully understood. Thioredoxin-1 (Trx1) is an antioxidant protein that can be cleaved into a peptide known as Thioredoxin-80 (Trx80), which modulates monocyte function in the periphery and shows anti-amyloidogenic properties in the brain. In this study we aimed to further clarify the biological function of this peptide and its regulation in the brain. We show that neurons are the main producers of Trx80 in the brain. Trx80 levels increase in vivo both in normal aging and in young APP NL-G-F mouse model of amyloid pathology. Trx80 levels were increased in neurons in primary culture treated with either rotenone or 27-hydroxycholesterol, what suggests that Trx80 production is stimulated upon oxidative stress. RNA-sequencing followed by differential gene expression analysis revealed that Trx80 induces microglia activation into a phenotype compatible with interferon response microglia. Finally, we determine that the induction of this microglia phenotype by Trx80 is Trem2-dependent. This study identifies Trx80 as a novel neuron-derived signaling mechanism that modulates microglia function under stress conditions. Strategies to regulate Trx80 levels could be beneficial against AD pathology. ### Competing Interest Statement The authors have declared no competing interest. * 27-OHC : 27-hydroxycholesterol; Aβ : Amyloid-beta; AD : Alzheimer’s Disease; Ank : Ankyrin1; ARM : Activated response microglia; bacTRAP : bacterial artificial chromosome – translating ribosome affinity purification; IRM : Interferon response microglia; Isg15 : Interferon-stimulated gene 15; Ifit2 : Interferon Induced Protein With Tetratricopeptide Repeats 2; Irf7 : Interferon Regulatory Factor 7; Nrf2 : Nuclear factor erythroid 2-related factor 2; Oasl2 : 2’-5’ oligoadenylate synthetase-like 2; Spp1 : Secreted Phosphoprotein 1; Trem2 : Triggering receptor expressed on myeloid cells 2; Trx1 : Thioredoxin-1 Trx80 : Thioredoxin-80.