Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases

Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb's impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation.