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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This post is Copyright: Laura Fernandez Garcia‐Agudo,
Zechuan Shi,
Ian F. Smith,
Enikö A. Kramár,
Katelynn Tran,
Shimako Kawauchi,
Shuling Wang,
Sherilyn Collins,
Amber Walker,
Kai‐Xuan Shi,
Jonathan Neumann,
Heidi Yahan Liang,
Celia Da Cunha,
Giedre Milinkeviciute,
Samuel Morabito,
Emily Miyoshi,
Narges Rezaie,
Angela Gomez‐Arboledas,
Adrian Mendoza Arvilla,
Daryan Iman Ghaemi,
Andrea J. Tenner,
Frank M. LaFerla,
Marcelo A. Wood,
Ali Mortazavi,
Vivek Swarup,
Grant R. MacGregor,
Kim N. Green | March 9, 2024