Amyloid-β (Aβ) immunotherapy induced microhemorrhages are linked to vascular inflammation and cerebrovascular damage in a mouse model of Alzheimer's disease

Abstract

Background: Anti-amyloid-β (Aβ) immunotherapy trials have revealed amyloid-related imaging abnormalities (ARIA) as the most prevalent and serious adverse events linked to pathological changes in cerebral vasculature. Recent studies underscore the critical involvement of perivascular macrophages and the infiltration of peripheral immune cells in regulating cerebrovascular damage. Specifically, Aβ antibodies engaged at cerebral amyloid angiopathy (CAA) deposits trigger perivascular macrophage activation and the upregulation of genes associated with vascular permeability. Nevertheless, further research is needed to understand the immediate downstream consequences of macrophage activation, potentially exacerbating CAA-related vascular permeability and microhemorrhages linked to Aβ immunotherapy.

Methods: This study investigates immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer's disease (AD) mouse model of microhemorrhage.

Results: In the present study, we have demonstrated that bapineuzumab murine surrogate (3D6) induces profound vascular damage, leading to smooth muscle cell loss and blood-brain barrier (BBB) breakdown. In addition, digital spatial profiling (DSP) reveals that distinct immune responses contribute to vascular damage with peripheral immune responses and perivascular macrophage activation linked to smooth muscle cell loss and vascular fibrosis, respectively. Finally, RNA in situ hybridization identifies two distinct subsets of Trem2⁺ macrophages representing tissue-resident and monocyte-derived macrophages around vascular amyloid deposits. Overall, these findings highlight multifaceted roles of immune activation and vascular damage in driving the development of microhemorrhage.

Conclusions: In summary, our study has established a significant link between CAA-Aβ antibody immune complex formation, immune activation and vascular damage leading to smooth muscle cell loss. However, the full implications of this cascade on the development of microhemorrhages requires further exploration. Additional investigations are warranted to unravel the precise molecular mechanisms leading to microhemorrhage, the interplay of diverse immune populations and the functional roles played by various Trem2⁺ macrophage populations in response to Aβ immunotherapy.