TREM2c·3G>A promotes aberrant microglial-endothelial signaling, impairs BBB integrity, and enhances Aβ and Tau accumulation

We identified a novel start-codon mutation in TREM2 ( TREM2 c·3G>A , M1I) that causes complete loss of TREM2 expression and is associated with early-onset Alzheimer’s disease (AD) in humans. This mutation triggers profound blood-brain barrier (BBB) impairment in both humans and mice, positioning BBB impairment as an early trigger rather than a downstream consequence of neurodegeneration in AD. Mechanistically, TREM2 deficiency causes NF-κB-driven upregulation of microglial CCL2, which activates CCR2 on endothelial cells and induces tight junction internalization. The resulting BBB compromise permits the leakage of peripheral pathological proteins, including β2-microglobulin, accelerating amyloid plaque formation and premature Tau pathology. Pharmacological inhibition of CCR2 and endothelial cell-specific Ccr2 knockdown restored BBB function and reduced amyloid plaque burden, highlighting this pathway as a tractable therapeutic target. Our findings establish a direct mechanistic link between microglial dysfunction, BBB breakdown, and pathogenic protein accumulation, thereby redefining the vascular role of TREM2 in neurodegenerative disease.