Lead Exposure in Developmental Ages Promotes Aβ Accumulation by Disturbing Aβ Transportation in Blood-Cerebrospinal Fluid Barrier/Blood-Brain Barriers and Impairing Aβ Clearance in the Liver

Biol Trace Elem Res. 2022 Aug;200(8):3702-3711. doi: 10.1007/s12011-021-02969-8. Epub 2021 Nov 17.

Abstract

Environmental lead exposure is closely related to the progression of Alzheimer's disease (AD). Our previous study has shown that exposure to lead could result in the cholesterol unbalance and increase amyloid-beta (Aβ) generation in the brain. However, the potential effect of lead exposure on Aβ transportation is poorly reported. In this study, we sought to explore whether lead exposure in developmental ages impaired the integrity of BCSFB and BBB, two highly vascularized structures in the brain in a rat model. The Aβ clearance in the liver was also assessed. Our results showed that lead treatment in developmental ages increased the number of TUNEL-positive apoptotic cells in rat choroid plexus and microvessels. Moreover, lead exposure markedly increased pro-inflammatory factors expression including TNF-α and IL-1β in rat choroid plexus and microvessels. Interestingly, lead treatment increased the expression of AQP-1 and reduced the expression of TTR, two key proteins associated with the functions of choroid plexus and microvessels. Additionally, the expressions of ABCB1, LRP-1, and RAGE, three major receptors responsible for Aβ transportation, were disturbed by developmental lead exposure. All these pathologies resulted in Aβ1-40 deposition within BCSFB and BBB and malfunctions of these two vascularized structures. Finally, we found that lead treatment remarkably inhibited the gene expression of LRP-1, which is responsible for Aβ endocytosis, in the liver tissue of the rat model. Collectively, our results provide the first evidence that developmental lead exposure induces Aβ deposition in BCSFB and BBB and impairs Aβ clearance in the liver, which would ultimately disturb Aβ transportation via choroid plexus/brain microvessels and facilitate Aβ deposition in the brain.

Keywords: Amyloid-beta; Blood-cerebrospinal fluid barrier; Blood–brain barrier; Lead; Neurotoxicology.

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Blood-Brain Barrier*
  • Brain / metabolism
  • Lead* / metabolism
  • Liver / metabolism
  • Rats

Substances

  • Amyloid beta-Peptides
  • Lead