Volume 18, Issue S3 e067665
BASIC SCIENCE AND PATHOGENESIS
Free Access

The role of Abca7 in late-onset Alzheimer’s disease animal models

Adrian L Oblak

Corresponding Author

Adrian L Oblak

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence

Adrian L Oblak, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.

Email: [email protected]

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Kevin P Kotredes

Kevin P Kotredes

The Jackson Laboratory, Bar Harbor, ME, USA

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Cynthia Ingraham

Cynthia Ingraham

Indiana University, Stark Neurosciences Research Institute, Indianapolis, IN, USA

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Paul R Territo

Paul R Territo

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

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Stacey J Sukoff Rizzo

Stacey J Sukoff Rizzo

University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

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Gregory W Carter

Gregory W Carter

The Jackson Laboratory, Bar Harbor, ME, USA

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Michael Sasner

Michael Sasner

The Jackson Laboratory, Bar Harbor, ME, USA

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Gareth R Howell

Gareth R Howell

The Jackson Laboratory, Bar Harbor, ME, USA

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Bruce T Lamb

Bruce T Lamb

Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA

Indiana University School of Medicine, Indianapolis, IN, USA

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MODEL-AD
First published: 20 December 2022

Abstract

Background

Alzheimer's disease (AD) and other neurodegenerative diseases are typified by a robust microglial-mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has extended this association, promoting ABCA7 as one of the most important risk genes of late-onset AD (LOAD), harboring both common and rare risk variants with relatively large effect on AD risk. Besides associations with disease status, genetic and epigenetic ABCA7 markers show significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human-based -omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism.

Method

To investigate the impact of Abca7 gene expression on microglia biology and disease pathology, we have generated Abca7A1527G mice on an APOE4.Trem2R47H (LOAD1) and APOE4.Trem2R47H.hAß (LOAD2) background. Cohorts of mice were established at JAX and IU and aged to either 4 and 12 months (LOAD1) or 4-, 12-, 18-, and 24-month. In vivo behavior and wellness assays included continuous activity monitoring, frailty assessment, open field, grip strength, spontaneous alternation, rotarod, delayed spatial novelty, episodic memory, and general health were completed as well as MRI and PET studies. Post-mortem studies included blood chemistry, immunohistochemistry, and molecular studies. Studies of transcriptomics and proteomics were also completed on brain tissue.

Result

Correlation of transcriptional profiling with human AMP-AD modules determined individual and synergistic effects with genetic risk factors. At 12 months of age, LOAD1.Abca7A1527G mice show similar correlations to LOAD in Consensus Cluster B (immune system), Consensus Cluster D (cell cycle), and Consensus Cluster E (organelle biogenesis). Neuropathology analysis in brain tissue is in progress, as are cytokine panels in brain homogenates and plasma of LOAD2. Abca7A1527G mice.

Conclusion

Our findings provide evidence that Abca7 plays an important role in LOAD and the addition of Abca7A1527G to a sensitized LOAD model (LOAD1 and LOAD2) more closely align phenotypes in the mouse to outcomes observed in human AD.