ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain

Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23790-23796. doi: 10.1073/pnas.1908529116. Epub 2019 Nov 5.

Abstract

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer's disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to AppNL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.

Keywords: ABCA7; Alzheimer’s disease; CD14; amyloid-β; immune response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / immunology*
  • Gene Expression Profiling
  • Haploinsufficiency*
  • Immunity, Innate / genetics
  • Mice
  • Mice, Transgenic
  • Microglia / immunology*
  • Transcriptome

Substances

  • ATP-Binding Cassette Transporters
  • Abca7 protein, mouse
  • Amyloid beta-Peptides