The Promyelocytic Leukemia Protein (PML) originally characterized as a tumor suppressor1, regulates various biological processes, such as gene transcription2, cell cycle3,4, DNA damage responses and apoptosis. In the nervous system, PML was shown to balance proliferation vs differentiation of neural progenitors5,6and have a neuroprotective action during early cerebral ischemia7,8. Recently, PML was categorized as a hub gene for AD and complexes9. Although PML protein was reported to regulate neuronal plasticity, misfolded protein degradation, aging and stress10, yet its role in Alzheimer’s disease (AD) has not been studied so far. To address this, we are employing in vivo neuroinflammation models as well as the 5xFAD mouse AD model. Intraperitoneal injection of Lipopolysaccharide (LPS) and intracerebroventricular injections of oAβ1-42 in WT and Pml-/- mice show in the absence of PML, a failure in microglia recruitment and activation leading to increased neurotoxicity in the hippocampus, as examined by immunohistochemistry, protein and gene expression analysis. Moreover, in two-month-old 5xFAD mice, PML nuclear expression is decreased in cortical neurons, while in advanced timepoints of pathology, PML is expressed in activated microglia in a diffused nuclear and cytoplasmic manner, both in the prefrontal cortex and the hippocampus. The above indicate a role for PML in amyloidogenic responses of microglia. To further study this, we currently generate Pml-/- mice bred to the 5xFAD transgenic background to examine how PML affects the disease course at the molecular and cognitive level.1.Hsu, K. & Kao, H. PML: Regulation and multifaceted function beyond tumor suppression. Cell Biosci 8, 5 (2018) doi:10.1186/s13578-018-0204-8.2.Gialitakis, M. et al., Gamma interferon-dependent transcriptional memory via relocalization of a gene locus to PML nuclear bodies. Mol. Cell. Biol. 30, 8 (2010) doi:10.1128/MCB.00906-09.3.Hadjimichael, C. et al., Promyelocytic Leukemia Protein Is an Essential Regulator of Stem Cell Pluripotency and Somatic Cell Reprogramming. Stem Cell Reports 8, 5 (2017) doi:10.1016/j.stemcr.2017.03.006.4.Sachini, N. et al. Promyelocytic leukemia protein (PML) controls breast cancer cell proliferation by modulating Forkhead transcription factors. Mol. Oncol. 13, 6 (2019) doi:10.1002/1878-0261.12486.5.Korb, E. & Finkbeiner, S. PML in the brain: From development to degeneration. Front. Oncol. 17, 3 (2013) doi:10.3389/fonc.2013.00242.6.Regad, T. et al., The tumor suppressor Pml regulates cell fate in the developing neocortex. Nat. Neurosci. 12, 2 (2009) doi:10.1038/nn.2251.7.Palibrk, V. et al. PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model. Cell Death Dis. 7, 7 (2016) doi:10.1038/cddis.2016.223.8.Amodeo, V. et al., A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS, Cell Rep. 20, 2 (2017) doi:10.1016/j.celrep.2017.06.047.9.Manners, H. N. et al., Intrinsic-overlapping co-expression module detection with application to Alzheimer’s Disease. Comput. Biol. Chem. 77,12 (2018)doi:10.1016/j.compbiolchem.2018.10.014.10.Marks, D. et al. Amyloid precursor protein elevates fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load. Acta Neuropathol. Commun. 9, 66 (2021) doi:10.1186/s40478-021-01174-x