Vascular damage is frequently observed in the brains of individuals with Alzheimer disease (AD), but its relationship with amyloid-β (Aβ) pathology, neurodegeneration and cognitive impairment is not fully understood. In a new study reported in Neuron, Katerina Akassoglou and colleagues show that cerebrovascular damage leads to deposition of the blood protein fibrinogen, which causes cognitive deficits through elimination of dendritic spines.
“Our research focuses on understanding how blood leaks in the CNS affect nervous system functions,” explains Akassoglou. “We were intrigued by the strong clinical correlations between vascular pathology and cognitive decline and became interested in deciphering the mechanisms that link this pathology with neuronal dysfunction.”
Dendritic spines are neuronal protrusions that receive synaptic input and are crucial for learning and memory. Using longitudinal two-photon imaging in the 5×FAD mouse model of AD, the investigators observed a loss of spines in the vicinity of fibrinogen deposits in the brain. Intriguingly, the fibrinogen deposits did not always colocalize with Aβ plaques, suggesting that the effects of fibrinogen on dendritic spines were not dependent on Aβ deposition.
Through a technique known as iDISCO (immunolabelling-enabled 3D imaging of solvent-cleared organs), the researchers visualized fibrinogen, Aβ and blood vessels in brain tissue from mice and patients with AD. These experiments confirmed the presence of focal fibrinogen deposition and blood–brain barrier (BBB) leakage, even in areas without Aβ pathology. “To our knowledge, this is the first 3D imaging of BBB disruption in the solvent-cleared brain,” comments Akassoglou.
Previous studies have shown that fibrinogen activates microglia by binding to the CD11b receptor, resulting in the generation of neurotoxic reactive oxygen species (ROS). Akassoglou and colleagues found that dendritic spine loss could be prevented by inhibiting ROS release. In addition, genetic disruption of the CD11b receptor binding site on the fibrinogen molecule reduced neurodegeneration and improved cognitive performance in 5×FAD mice.
“The finding that fibrinogen deposition induces pathogenic microglial activation, leading to ROS release and dendritic spine loss, might open up a new pathway for therapeutic intervention to suppress vascular-driven neurodegeneration,” concludes Akassoglou. “In addition, fibrinogen and fibrin could be useful biomarkers for sensitive detection of vascular abnormalities in neurodegenerative diseases.”
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Ryu, J. K. et al. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat. Immunol. 19, 1212–1223 (2018)
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Wood, H. Fibrinogen links vascular pathology to cognitive decline. Nat Rev Neurol 15, 187 (2019). https://doi.org/10.1038/s41582-019-0154-8
Neuroscience & Biobehavioral Reviews (2020)