Physiological Emergence of Amyloid-β During the Acute Cerebral Stress of Mechanical Ventilation Reduces Peri-Hippocampal and Cortical Blood-Brain Barrier Permeability and Neuronal Injury

Abstract

Background: Prior published data show that short-term mechanical ventilation contributes to pathological hallmarks of Alzheimer’s Disease (AD) by increasing cerebral accumulation of the amyloid-β1-40 (Aβ1-40) peptide and neuroinflammation while unexpectedly decreasing blood-brain barrier permeability. In this study, we hypothesized that the acute cerebral immunochallenge of mechanical ventilation promotes physiological emergence of Aβ1-40 to regions of acute vascular disruption, resulting in reduced neuronal injury.Methods: Immunohistology was used to assess the regional relationship between cerebral Aβ1-40 accumulation, acute vascular disruption, and neuronal inflammation and apoptosis as measured by cleaved caspase-3 (CC3) expression from mechanically ventilated double transgenic AD-model (ADtg) mice and compared to mechanically ventilated wild-type (WT) controls.Results: There was significantly decreased expression of CC3 in regions of cortical and hippocampal Aβ1-40 accumulation in mechanically ventilated ADtg animals (p=0.0224). In contrast, CC3 expression was significantly increased in cortical and hippocampal regions of mechanically ventilated WT controls (p=0.0260). Aβ1-40 accumulation occurred in regions of acute vascular disruption in a characteristic banding pattern and reduced blood-brain barrier permeability. The banding pattern was significantly increased in ADtg mice subjected to mechanical ventilation compared to non-mechanically ventilated ADtg mice (p=0.0002). Additionally, no evidence of irreversible neurological injury is seen in mechanically ventilated ADtg and WT mice, as demonstrated by the absence of TUNEL positive staining. Conclusions: This study provides first evidence that acute short-term mechanical ventilation-induced cerebral immunochallenge promotes physiological emergence of Aβ1-40 to reduce blood-brain barrier permeability and neuronal injury. While it is expected that sustained or long-term activation of this normally protective pathway leads to dysregulated Aβ1-40 accumulation, neurodegeneration, and cognitive impairment, these data suggest that a window of opportunity may exist within which implementation of timely interventions may limit cognition-relevant cerebral injury.