Promyelocytic leukemia protein promotes neuroprotection in a mouse model of Alzheimer’s disease by modulating the microglial inflammatory response

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid plaque deposition, neurofibrillary tangles, neuroinflammation and synaptic dysfunction. The Promyelocytic leukemia protein (PML) and its cognate nuclear bodies (PML-NB) have emerged as critical regulators of the nervous system, contributing to the regulation of neocortical development, neuronal survival, protein homeostasis and cellular stress responses. PML-NB have also been implicated in the solubility and clearance of pathological aggregates in neurodegenerative diseases. However, the role of PML in AD pathogenesis and the impact of its loss in amyloid pathology remain largely unknown. To investigate the role of PML in neuroinflammation we used intracerebroventricular (ICV) injections of oligomeric amyloid beta 1-42 (oAβ1-42), 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. Pml-/- mice displayed reduced recruitment and activation of microglia following intracerebroventricular οΑβ 1-42 injections accompanied by deregulated expression of disease-associated microglia genes. Consistently, PML-deficient primary microglia exhibited reduced phagocytosis, activation, viability and impaired cytokine responsiveness following β-amyloid challenge. In the 5xFAD model, PML loss increased Aβ accumulation, neuronal loss and astrocyte reactivity while attenuating microglial activation and lysosomal function. Hippocampal RNA-seq revealed extensive sex-dependent transcriptomic remodeling characterized by suppression of immune, synaptic and metabolic pathways, together with impaired induction of disease-associated microglial genes. These molecular and cellular alterations were accompanied by worsening hippocampus-dependent memory deficits and increased impulsive behavior. PML loss exacerbates multiple aspects of AD pathophysiology including amyloid deposition, anti-inflammatory responses, neuronal loss and cognitive decline. Our findings identify PML as a previously unrecognized regulator of microglial function and amyloid pathology and suggest that PML-dependent pathways may represent therapeutic targets for Alzheimer's disease.