Promyelocytic Leukemia Protein Promotes Neuroprotection in a mouse model of Alzheimer’s Disease by Modulating the Microglial Inflammatory Response

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by amyloid deposition, neurofibrillary tangles, neuroinflammation and synaptic dysfunction. The Promyelocytic leukemia protein (PML) and the cognate nuclear bodies (PML-NB) have emerged as critical regulators of the nervous system, regulating neocortex development, neuronal survival, protein homeostasis and protection from stress. PML-NB have been implicated in the solubility of pathological aggregates in Neurodegenerative Diseases (NDD). However, the impact of PML on AD progression and whether its loss affects amyloid pathology remain unknown. Methods To investigate the role of PML in neuroinflammation we used intracerebroventricular (ICV) injections of oligomeric amyloid beta 1–42 (oAβ ₁₋₄₂ ), in WT and Pml-/- mice and primary microglia cultures derived from these genotypes. To explore the role of PML in AD pathology we employed phenotypic, transcriptomic and behavioral analyses of WT, Pml-/- , 5xFAD and 5xFAD Pml-/- mice. Results Pml-/- mice displayed reduced recruitment and activation of microglia in the vicinity of οΑβ ₁₋₄₂ injection, accompanied by deregulated expression of disease-associated microglia (DAM) genes. Consistently, Pml-/- primary microglial cultures exhibit reduced phagocytosis, activation, viability and impaired cytokine responsiveness following β-amyloid challenge. PML depletion in 5xFAD mice accelerates Aβ accumulation, impairs microglial activation, lysosomal acidification and recruitment to amyloid plaques while enhances astrocyte reactivity and neuronal degeneration. Hippocampal transcriptomic analyses reveal sex-dependent effects of PML loss, with downregulation of pathways related to cell migration, axonogenesis and synapse organization in 5xFAD Pml-/- females and peroxisomal functions, DNA repair and immune responses, in 5xFAD Pml-/- males. Both sexes show suppression of immune response genes and deregulated expression of DAM genes. PML depletion increases impulsivity and hippocampus-dependent behavioral abnormalities in the context of Aβ pathology, highlighting a role for PML in maintaining cognitive function. Conclusions PML loss exacerbates multiple aspects of AD pathophysiology including amyloid deposition, impaired anti-inflammatory responses, neurotoxicity and cognitive performance. Our findings identify PML as a key regulator for microglial homeostasis and neuroprotective functions in amyloid pathology. Through its actions in microglia, PML emerges as an effector and a marker of aging and neurodegeneration. Restoring or enhancing its activity may represent a promising therapeutic strategy to preserve neuronal function in AD.