ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain

Tomonori Aikawa, Yingxue Ren, Yu Yamazaki, Masaya Tachibana, Madeleine R. Johnson, Casey T. Anderson, Yuka A. Martens, Marie Louise Holm, Yan W. Asmann, Takashi Saito, Takaomi C. Saido, Michael L. Fitzgerald, Guojun Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)23790-23796
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number47
DOIs
StatePublished - Jan 1 2019

Fingerprint

Alzheimer Disease
Amyloid
Brain
Nonsense Codon
Microglia
Knockout Mice
Breeding
Lipopolysaccharides
Immune System
Phospholipids
Homeostasis
Alleles
Cholesterol
Pathology
Inflammation
Injections
Genes
Therapeutics

Keywords

  • ABCA7
  • Alzheimer’s disease
  • Amyloid-β
  • CD14
  • Immune response

ASJC Scopus subject areas

  • General

Cite this

ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain. / Aikawa, Tomonori; Ren, Yingxue; Yamazaki, Yu; Tachibana, Masaya; Johnson, Madeleine R.; Anderson, Casey T.; Martens, Yuka A.; Holm, Marie Louise; Asmann, Yan W.; Saito, Takashi; Saido, Takaomi C.; Fitzgerald, Michael L.; Bu, Guojun; Kanekiyo, Takahisa.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 47, 01.01.2019, p. 23790-23796.

Research output: Contribution to journalArticle

Aikawa, T, Ren, Y, Yamazaki, Y, Tachibana, M, Johnson, MR, Anderson, CT, Martens, YA, Holm, ML, Asmann, YW, Saito, T, Saido, TC, Fitzgerald, ML, Bu, G & Kanekiyo, T 2019, 'ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 47, pp. 23790-23796. https://doi.org/10.1073/pnas.1908529116
Aikawa, Tomonori ; Ren, Yingxue ; Yamazaki, Yu ; Tachibana, Masaya ; Johnson, Madeleine R. ; Anderson, Casey T. ; Martens, Yuka A. ; Holm, Marie Louise ; Asmann, Yan W. ; Saito, Takashi ; Saido, Takaomi C. ; Fitzgerald, Michael L. ; Bu, Guojun ; Kanekiyo, Takahisa. / ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 47. pp. 23790-23796.
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