Editors' ChoiceAlzheimer’s Disease

Neuronal connections killed in cold blood

See allHide authors and affiliations

Science Translational Medicine  27 Feb 2019:
Vol. 11, Issue 481, eaax0153
DOI: 10.1126/scitranslmed.aax0153


Loss of neuronal junctions triggered by a clotting factor promotes cognitive decline in Alzheimer’s disease.

Disruption of the blood-brain barrier (BBB) and consequent leakage of blood proteins into the brain occurs early in Alzheimer’s Disease (AD) and has been suggested to promote cognitive decline independent of β-amyloid (AB) aggregation. Fibrinogen, a blood clotting factor, deposits in the AD brain near blood vessels and Aβ plaques, with several studies suggesting its contribution to disease burden. Merlini and colleagues have taken this research a step further by causally implicating fibrinogen in the loss of synapses.

Using a technique to clear large volumes of tissue combined with longitudinal fluorescence imaging, the authors found fibrinogen deposits both near and distal from Aβ plaques in the brains of two different AD mouse models. Interestingly, synaptic loss was observed near fibrinogen deposits, even in the absence of surrounding Aβ plaques. Supporting the idea that this clotting factor alone could induce loss of synapses, injection of fibrinogen or plasma, but not plasma devoid of fibrinogen, elicited synaptic loss in non-AD mice. Fibrinogen activates microglia, a nonneuronal brain cell type with immune function, by binding to the receptor CD11b. In mice lacking CD11b, fibrinogen injection did not cause a loss of synapses, indicating that the synaptic deficits were mediated by microglia. Similarly, blockade of reactive oxygen species’ release, which follows microglia activation, also abrogated synapse loss. Importantly, in AD mice crossed with another mouse strain that produces functional fibrinogen lacking the binding site for CD11b, the authors showed no cognitive decline, less pronounced activation of microglia, more moderate neuronal loss, and lower numbers of Aβ plaques.

Several questions arising from the present study will need to be addressed in future research—for instance, how Aβ and fibrinogen may synergize to cause loss of synapses and neuronal death. Nevertheless, the finding that fibrinogen activation of microglia is sufficient to cause synapse loss in the absence of Aβ has profound clinical implications, not only for AD, but also for other diseases with BBB disruption, such as vascular dementia.

Highlighted Article

View Abstract

Navigate This Article