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BIN1K358R suppresses glial response to plaques in mouse model of Alzheimer's disease.
Garcia-Agudo, Laura Fernandez; Shi, Zechuan; Smith, Ian F; Kramár, Enikö A; Tran, Katelynn; Kawauchi, Shimako; Wang, Shuling; Collins, Sherilyn; Walker, Amber; Shi, Kai-Xuan; Neumann, Jonathan; Liang, Heidi Yahan; Da Cunha, Celia; Milinkeviciute, Giedre; Morabito, Samuel; Miyoshi, Emily; Rezaie, Narges; Gomez-Arboledas, Angela; Arvilla, Adrian Mendoza; Ghaemi, Daryan Iman; Tenner, Andrea J; LaFerla, Frank M; Wood, Marcelo A; Mortazavi, Ali; Swarup, Vivek; MacGregor, Grant R; Green, Kim N.
Afiliação
  • Garcia-Agudo LF; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Shi Z; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Smith IF; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Kramár EA; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Tran K; 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.
  • Wang S; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Collins S; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Walker A; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Shi KX; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Neumann J; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Liang HY; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, California, USA.
  • Da Cunha C; Department of Developmental and Cell Biology, University of California, Irvine, California, USA.
  • Milinkeviciute G; Center for Complex Biological Systems, University of California, Irvine, California, USA.
  • Morabito S; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Miyoshi E; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Rezaie N; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Gomez-Arboledas A; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Arvilla AM; Department of Developmental and Cell Biology, University of California, Irvine, California, USA.
  • Ghaemi DI; Center for Complex Biological Systems, University of California, Irvine, California, USA.
  • Tenner AJ; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • LaFerla FM; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • Wood MA; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Mortazavi A; Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
  • Swarup V; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
  • MacGregor GR; Department of Molecular Biology & Biochemistry, University of California, Irvine, California, USA.
  • Green KN; Department of Pathology and Laboratory Medicine, University of California, Irvine, California, USA.
Alzheimers Dement ; 20(4): 2922-2942, 2024 04.
Article em En | MEDLINE | ID: mdl-38460121
ABSTRACT

INTRODUCTION:

The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.

METHODS:

To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.

RESULTS:

The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant.

DISCUSSION:

The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. HIGHLIGHTS BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Animals / Humans Idioma: En Revista: Alzheimers Dement Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Animals / Humans Idioma: En Revista: Alzheimers Dement Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos