Neuroinflammation and vascular pathology in Alzheimer's Disease: The NRF2/HO-1 axis as a modulator of microglial phenotypes.

Abstract

Alzheimer's disease (AD) frequently co-occurs with vascular pathology, and this overlap is increasingly recognized as a major driver of cognitive decline in mixed dementia and vascular cognitive impairment and dementia (VCID). Disruption of the neurovascular unit (NVU) creates a perivascular microenvironment rich in inflammatory and oxidative cues that can instruct microglial state transitions. In this review, we argue that perivascular microglia represent a key "decision hub" at the neurovascular interface, where shifts from homeostatic surveillance toward disease-associated microglia (DAM) programs influence both amyloid handling and the amplification of neuroinflammation. We propose that the NRF2/HO-1 axis functions as a context-sensitive phenotype-control module in these niches: NRF2 integrates oxidative/electrophilic stress through KEAP1 and signaling-dependent regulation through the GSK-3/β-TrCP pathway, thereby shaping transcriptional programs that govern inflammatory tone, redox balance, iron handling, and phagocytic competence. Within this network, HO-1 emerges as a key effector because its metabolites, carbon monoxide, bile pigments, and iron-ferritin responses, can modulate innate immune signaling and, potentially, paracrine communication across NVU cell types. We synthesize evidence linking NVU dysfunction to perivascular microglial activation and discuss how NRF2/HO-1 engagement may remain compensatory in early or acute settings yet become maladaptive under chronic stress or prolonged HO-1 activity. Finally, we outline therapeutic implications of targeting NRF2/HO-1 to reprogram perivascular microglia toward protective DAM functions, emphasizing target engagement, timing, dose, and cell-type specificity as critical determinants of translational success.