ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain.
Tomonori AikawaYingxue RenYu YamazakiMasaya TachibanaMadeleine R JohnsonCasey T AndersonYuka A MartensMarie-Louise HolmYan W AsmannTakashi SaitoTakaomi C SaidoMichael L FitzgeraldGuojun BuTakahisa KanekiyoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
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 App NL-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.
Keyphrases
- immune response
- liver failure
- inflammatory response
- drug induced
- respiratory failure
- neuropathic pain
- toll like receptor
- lps induced
- lipopolysaccharide induced
- poor prognosis
- aortic dissection
- gene expression
- white matter
- spinal cord injury
- metabolic syndrome
- dendritic cells
- type diabetes
- resting state
- dna methylation
- adipose tissue
- hepatitis b virus
- genome wide
- cognitive decline
- insulin resistance
- early onset
- ultrasound guided
- acute respiratory distress syndrome
- binding protein
- blood brain barrier
- skeletal muscle
- high glucose