Neuron
Volume 101, Issue 6, 20 March 2019, Pages 1099-1108.e6
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Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model

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Highlights

  • Fibrinogen is a blood-derived inducer of spine elimination

  • Fibrinogen promotes synapse loss in AD mice

  • 3D volume imaging of BBB disruption and Aβ in cleared human AD brain

  • Genetic inhibition of fibrinogen-CD11b binding improves cognition in AD mice

Summary

Cerebrovascular alterations are a key feature of Alzheimer’s disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling 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. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.

Keywords

fibrin
blood-brain barrier
coagulation
innate immunity
neurovascular
dementia
multiple sclerosis
iDISCO
complement
dendritic spines

Cited by (0)

4

Present address: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA

5

Present address: MindImmune Therapeutics, Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA

6

Lead Contact