THE ROLE OF ZFYVE21 IN CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER'S DISEASE

项目总结

PROJECT SUMMARY Cerebral amyloid angiopathy (CAA) is an untreatable vasculopathic condition affecting a vast majority of patients with Alzheimer's disease (AD). In CAA, fibrils of Aβ(1-40) deposit in cerebral vessels and promote the development of stenotic lesions, intracranial hemorrhages, and perivascular inflammation. These CAA- associated vascular pathologies show strong linear correlations with the severity of AD, and are thus believed to promote neurodegeneration and contribute to AD dementia. How CAA develops is poorly understood and defining mechanism(s) related to its pathogenesis will define new vascular-based strategies for treating AD. Complement (C') are a conserved system of plasma proteins involved in host defense. Upon activation, C' proteins self-assemble into heterodimeric structures called membrane attack complexes (MAC) that insert as transmembranous pores into target cell membranes. MAC colocalize with Aβ(1-40) deposits in CAA- affected vessels showing evidence of EC activation, and inhibition of complement protein C5, which prevents MAC assembly, blocks progression of AD in a murine mouse model with CAA. In solid organ transplantation, we identified ZFYVE21 as a novel MAC-induced Rab5 effector that activated non-canonical NF-κB, NLRP3 inflammasomes, and canonical NF-κB to mediate endothelial cell (EC) activation and development of vasculopathic lesions. As C' activation, EC activation, and similar forms of vasculopathy are observed in CAA, we explored whether ZFYVE21 signaling may play a role in the development of this condition. We thus embarked on studies defining a role for ZFYVE21 signaling in CAA based on the hypothesis Aβ fibrils activate C' on cerebrovascular ECs to induce ZFYVE21-mediated EC activation to promote CAA vasculopathy and CAA-related neurodegeneration in AD. AD biopsies showed strong staining for MAC, ZFYVE21, and its downstream pathways in Aβ-laden microvessels affected by CAA. To develop mechanism(s) to explain these findings, we optimized an in vitro model of Aβ-induced C' activation that was sufficiently robust to confirm ZFYVE21-mediated signaling in human cerebrovascular endothelial cells (HBMECs). We developed new in vitro and in vivo model systems to examine the functional significance of ZFYVE21 signaling with regards to EC activation, barrier permeability, and macrophage recruitment. In 3 unified aims, we will extend findings from our original proposal to investigate ZFYVE21-mediated mechanisms of EC activation in CAA. Our aims will form the basis for a long-term program invested in studying how C' mediates vascular pathologies to further neurodegeneration in AD.