| First Author | Butler CA | Year | 2024 |
| Journal | Alzheimers Dement | Volume | 20 |
| Issue | 7 | Pages | 4914-4934 |
| PubMed ID | 38506634 | Mgi Jnum | J:350686 |
| Mgi Id | MGI:7664335 | Doi | 10.1002/alz.13783 |
| Citation | Butler CA, et al. (2024) The Abca7(V1613M) variant reduces Abeta generation, plaque load, and neuronal damage. Alzheimers Dement 20(7):4914-4934 |
| abstractText | BACKGROUND: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS: CRISPR-Cas9 was used to generate an Abca7(V1613M) variant in mice, modeling the homologous human ABCA7(V1599M) variant, and extensive characterization was performed. RESULTS: Abca7(V1613M) microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7(V1613M) mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7(V1613M) mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Abeta) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Abeta-associated inflammation, gliosis, and neuronal damage. DISCUSSION: Overall, homozygosity for the Abca7(V1613M) variant influences phagocytosis, response to inflammation, lipid metabolism, Abeta pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. HIGHLIGHTS: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice. |
