Blood‐brain barrier leak precedes brain histopathology and cognitive impairment in mild hyperhomocysteinemia

Abstract

Hyperhomocysteinemia (HHcy) is associated with blood‐brain barrier (BBB) permeability and Alzheimer's disease. We explored the relation among BBB permeability, brain histopathology, amyloid‐beta (Abeta) transport and deposition and cognitive function in HHcy. We used C57Bl/6 mice with heterozygous deletion of cystathionine β‐synthase (Het) and wild‐type littermates (WT) [young: 5–9 mos; old: 12–29 mos]. BBB permeability was greater in Het compared to WT at all ages (p<0.05). Old, but not young, Het mice had greater cognitive impairment than any other group in Morris water maze tests (p<0.05). Old Het mice also showed greater inflammation (CD45+ and VCAM+) and leukoaraiosis in the fornix compared to WT (p<0.05) with concomitant evidence of disrupted autophagy in the hippocampus (increased caspase‐cleavage of beclin‐1; p<0.05). There were no differences for these measures among young or WT mice. There was no difference in levels of Abeta transporters in isolated cerebral microvessels (RAGE, LRP‐1, Pgp) or Abeta deposition in the brain with age or by Hcy level.Conclusionin mild HHcy, increased permeability of the BBB precedes the onset of brain histopathology and cognitive dysfunction, which is independent of Abeta deposition. Protecting the BBB from the effects of Hcy early in life may reduce the incidence or severity of cognitive decline later in life. Supported by NIH HL106548 (SEB).