Astrocyte lactoferrin deficiency affects the construction and function of spinal neurons by regulating cholesterol metabolism

Abstract

Astrocytes play pivotal roles in central nervous system (CNS) homeostasis, with emerging evidence implicating astrocyte-derived lactoferrin (Lf) in neurodevelopmental and neurodegenerative processes. This study investigates Lf's functional significance in spinal cord integrity using astrocyte-specific Lf knockout (cKO) mice. Behavioral analyses of 1-month-old male cKO mice revealed impaired motor coordination (increased balance beam scores and prolonged pole-climbing latency) and delayed nociceptive responses (increased thermal withdrawal latency). Morphological assessments demonstrated neuron-specific pathology: motor neurons exhibited atrophy and reduced Nissl substance staining, spinal ganglion cells showed quantitative depletion with vacuolar degeneration, and protein expression analyses confirmed declines in neuronal markers (NeuN), synaptic components (SNAP25, PSD95), axonal and myelin related proteins (NF-L, MBP), and neurotransmitter transporters (AChE). Notably, glial cell populations remained unaffected. Mechanistic investigations identified reduced spinal cholesterol content accompanied by downregulation of cholesterol biosynthesis and transport regulators (Srebp2, HMGCR, ApoE, ABCA1) and activation of AMP-activated protein kinase (AMPK). These findings establish astrocytic Lf as a critical modulator of cholesterol metabolism essential for maintaining neuronal structural and functional integrity in the spinal cord. The discovered Lf-cholesterol regulatory axis provides novel insights into the pathogenesis of spinal cord disorders and highlights potential therapeutic targets for neurodegenerative conditions.