Basic Science and Pathogenesis - Part 1.

Abstract

Cerebrovascular alterations and innate immune activation are key features of Alzheimer's disease (AD). However, the mechanisms that link blood-brain barrier disruption to neurodegeneration are poorly understood and well-defined druggable targets at the neurovascular interface are limited. We identified the blood coagulation factor fibrinogen as necessary and sufficient for the induction of pathogenic neuroinflammation in neurologic diseases1. Fibrinogen induces spine elimination and promotes cognitive deficits in AD mouse models mediated by oxidative stress induction in microglia2, 3. Volume imaging in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. We developed a first-in-class fibrin-targeting immunotherapy to selectively inhibit fibrin-induced inflammation without interfering with its beneficial coagulation effects4. Fibrin-targeting immunotherapy entered the CNS, bound to fibrin, and inhibited amyloid-driven neurotoxicity and neurotoxic inflammatory gene programs in AD mice. Thus, fibrinogen links cerebrovascular damage with immune-mediated neurodegeneration and fibrin therapeutics may have important therapeutic implications inhibiting vascular-driven neurodegeneration in AD and related conditions. 1. Petersen et al., Nat Rev Neurosci. 2018, 19:283-301 2. Merlini et al. Neuron 2019, 101:1099-1108 3. Mendiola et al. Nat Immunol 2020, 21:513-524 4. Ryu et al. Nat Immunol 2018, 19:1212-1223.