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The Abca7V1613M variant reduces Aß generation, plaque load, and neuronal damage.
Butler, Claire A; Mendoza Arvilla, Adrian; Milinkeviciute, Giedre; Da Cunha, Celia; Kawauchi, Shimako; Rezaie, Narges; Liang, Heidi Y; Javonillo, Dominic; Thach, Annie; Wang, Shuling; Collins, Sherilyn; Walker, Amber; Shi, Kai-Xuan; Neumann, Jonathan; Gomez-Arboledas, Angela; Henningfield, Caden M; Hohsfield, Lindsay A; Mapstone, Mark; Tenner, Andrea J; LaFerla, Frank M; Mortazavi, Ali; MacGregor, Grant R; Green, Kim N.
Affiliation
  • Butler CA; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Mendoza Arvilla A; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Milinkeviciute G; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Da Cunha C; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Kawauchi S; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Rezaie N; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Liang HY; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Javonillo D; Department of Developmental and Cell Biology, University of California, Irvine, California, USA.
  • Thach A; Center for Complex Biological Systems, University of California, Irvine, California, USA.
  • Wang S; Department of Developmental and Cell Biology, University of California, Irvine, California, USA.
  • Collins S; Center for Complex Biological Systems, University of California, Irvine, California, USA.
  • Walker A; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Shi KX; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Neumann J; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Gomez-Arboledas A; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Henningfield CM; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Hohsfield LA; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Mapstone M; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Tenner AJ; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • LaFerla FM; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Mortazavi A; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • MacGregor GR; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Green KN; Department of Neurology, University of California, Irvine, California, USA.
Alzheimers Dement ; 20(7): 4914-4934, 2024 07.
Article in En | MEDLINE | ID: mdl-38506634
ABSTRACT

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 Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.

RESULTS:

Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aß) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aß-associated inflammation, gliosis, and neuronal damage.

DISCUSSION:

Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aß 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Mice, Transgenic / Amyloid beta-Peptides / ATP-Binding Cassette Transporters / Plaque, Amyloid / Alzheimer Disease Limits: Animals / Humans Language: En Journal: Alzheimers Dement Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Mice, Transgenic / Amyloid beta-Peptides / ATP-Binding Cassette Transporters / Plaque, Amyloid / Alzheimer Disease Limits: Animals / Humans Language: En Journal: Alzheimers Dement Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States