Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model

Neuron. 2019 Mar 20;101(6):1099-1108.e6. doi: 10.1016/j.neuron.2019.01.014. Epub 2019 Feb 5.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology
  • Animals
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Brain / metabolism*
  • Brain / physiology
  • Brain / physiopathology
  • CD11b Antigen / metabolism
  • CD18 Antigens / metabolism
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / pathology
  • Cognitive Dysfunction / physiopathology
  • Dendritic Spines / metabolism*
  • Dendritic Spines / pathology
  • Disease Models, Animal
  • Fibrinogen / metabolism*
  • Humans
  • Imaging, Three-Dimensional
  • Mice
  • Microglia / metabolism*
  • Plaque, Amyloid / metabolism*
  • Plaque, Amyloid / pathology
  • Reactive Oxygen Species / metabolism


  • CD11b Antigen
  • CD18 Antigens
  • Reactive Oxygen Species
  • Fibrinogen