ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-β Peptide Efflux in an in Vitro Model of the Blood-Brain Barrier

J Alzheimers Dis. 2018;64(4):1195-1211. doi: 10.3233/JAD-170883.

Abstract

The role of ABCA7 in brain homeostasis and Alzheimer's disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell ® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 expression and a decrease in APOE secretion. In vitro, these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage, Lrp1, Abcb1, Abcc1, and Abcg2. Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein's involvement in cholesterol metabolism and amyloid clearance at the BBB.

Keywords: ABCA7; Alzheimer’s disease; Aβ peptides; blood-brain barrier; cholesterol metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Apolipoproteins E / genetics
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Brain / cytology
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Claudins / genetics
  • Claudins / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Endothelial Cells / drug effects
  • Homeostasis / drug effects
  • Homeostasis / physiology*
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Transfection
  • Zonula Occludens-1 Protein / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Abca7 protein, mouse
  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Claudins
  • RNA, Messenger
  • RNA, Small Interfering
  • Tjp1 protein, mouse
  • Zonula Occludens-1 Protein
  • Cholesterol