Loss of TREM2 function in mice leads to blood-brain barrier impairment, pathological leakage, and cognitive deficits due to microglial CCL2 upregulation

Abstract

Abstract Blood-brain barrier (BBB) impairment, which causes leakage of harmful peripheral substances into the brain, is an early indicator of Alzheimer’s disease (AD). Microglia are known to regulate BBB integrity, but the underlying mechanisms of this process remain unclear. We here analyzed BBB permeability and structural integrity in mice. Loss of TREM2 function was found to impair the structural integrity of the BBB; TREM2-deficient microglia showed CCL2 upregulation via activation of the NFκB pathway. The CCL2-CCR2 axis reduced the expression of endothelial tight junction proteins, including claudin-5, occludin, and ZO-1. BBB impairment led to increased leakage of amyloid β (Aβ) and β2-microglobulin (β2M) from peripheral tissues into the brain parenchyma, accelerating the formation of Aβ plaques and subsequent cognitive decline. Importantly, pharmacological blocking of CCR2 restored the BBB integrity, prevented peripheral Aβ deposition in the brain, and improved cognitive function in Trem2-knockout mice. Collectively, these results suggested that loss of TREM2 function induced BBB impairment and accelerated AD progression. Our study thus establishes TREM2 as a critical target for future studies of treatments to prevent and mitigate the effects of AD.