Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling.

Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, and , where mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection.

Basic Science and Pathogenesis.

Background: Genome-Wide Association Studies (GWAS) identified ApoE4 and Trem2*R47H as two of the strongest genetic risk factors for late-onset Alzheimer's Disease (LOAD). As part of our efforts to develop mouse models that better recapitulate LOAD, at Model Organism Development & Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium at University of California - Irvine, we have created a triple homozygous mouse model that combines our previously developed hAb-KI mice (Jackson Lab #031050), Trem2 (Jackson Lab #034036) and a humanized ApoE4 (Jackson Lab #027894), to evaluate the interactions between aging, hAPOE4, TREM2*R47H, and hAb.

Method: By breeding the hAb-KI, hApoE4 and Trem2, we obtained triple homozygous (HO) mice and we then generated four different groups: WT (C57BL6/J), hAb-KI HO, hAb-KI HO;hApoE4 HO and hAb-KI HO;hApoE4 HO;Trem2 HO.

Basic Science and Pathogenesis.

Background: A case study on a PSEN1 (E280A) carrier with APOECh (R136S) mutation revealed changes in APOE protein function led to a protective effect on AD outcomes. Notably, there is an intriguing disparity between the two hallmark pathologies: a reduction in tauopathy but no change in plaque burden. Given that the APOE protein is predominantly produced by astrocytes and activated microglia, and the APOE gene is among the disease-associated microglia (DAM) genes, it is conceivable that the variance in pathological outcomes may be rooted in the glial response.

Basic Science and Pathogenesis.

Background: Genome-Wide Association Studies (GWAS) implicate SPI1 (PU.1) as a risk factor for late-onset Alzheimer's Disease (LOAD). Within the brain, SPI1 encodes a microglia-specific transcription factor, necessary for microglial proliferation and activation.