The ABC Transporter A7 Modulates Neuroinflammation Via NLRP3 Inflammasome in Alzheimer's Disease Mice

Overview

Journal Alzheimers Res Ther

Date 2025 Jan 28

PMID 39871385

Authors

Irene Santos-Garcia

Pablo Bascunana

Mirjam Brackhan

Maria Villa

Ivan Eiriz

Thomas Bruning

Jens Pahnke

Affiliations

Soon will be listed here.

Abstract

Background: Specific genetic variants in the ATP-binding cassette transporter A7 locus (ABCA7) are associated with an increased risk of Alzheimer's disease (AD). ABCA7 transports lipids from/across cell membranes, regulates Aβ peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome.

Methods: We developed the first humanized, Cre-inducible ABCA7 knock-in mouse model, crossbred it with the APPPS1-21 β-amyloidosis model, and generated constitutive ABCA7 and microglia Cx3cr1-specific conditional ABCA7 AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods.

Results: Constitutive knockout of the Abca7 gene in APPPS1 mice increased the levels of Aβ42 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1β and TNFα. Interestingly, microglia-specific ABCA7 restored Aβ peptide levels and IBA1 and GFAP and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7 microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes.

Conclusions: Our data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.

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