Mechanistic insights into hypoxic exposure-induced cognitive impairment: The role of choroid plexus barrier disruption and M1 macrophage polarization in mice.

Abstract

The central nervous system (CNS) exhibits high sensitivity to environmental oxygen fluctuations. Hypoxic exposure may induce cognitive impairment, manifested as mental sluggishness, confusion, or loss of consciousness, and can cause irreversible CNS damage. The underlying mechanisms remain incompletely elucidated. The choroid plexus constitutes the fundamental structure enabling blood-cerebrospinal fluid barrier (BCSFB) functionality. Maintenance of immunomodulatory homeostasis within the choroid plexus microenvironment is critical for preserving CNS integrity. This study investigates the impact of simulated 6000-m altitude hypoxic exposure on murine choroid plexus and cognitive function. Hypoxic exposure induces cognitive dysfunction in mice, wherein choroid plexus barrier impairment serves as a critical pathophysiological trigger. Post-hypoxia, aberrant AMPK pathway signaling and elevated oxidative stress within the choroid plexus drive pathological M1 macrophage polarization, thereby disrupting barrier integrity and ultimately causing cognitive deficits. Our findings establish a mechanistic cascade: Hypoxic exposure → M1 macrophage polarization → Choroid plexus barrier disruption → CNS cognitive impairment. This delineated pathway highlights potential therapeutic value for targeting hypoxic stress-induced cognitive disorders.