Researchers at the Gladstone Institutes report that fibrinogen is responsible for a series of molecular and cellular events that can destroy connections between neurons in the brain and result in cognitive decline. Senior investigator Katerina Akassoglou, PhD, and her team used imaging technology to study both mouse brains and human brains from patients with Alzheimer’s disease. They also produced the first three-dimensional volume imaging showing that blood-brain barrier leaks occur in Alzheimer’s disease.

In their study (“Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model“), published in Neuron, the scientists found that fibrinogen, after leaking from the blood into the brain, activates the brain’s immune cells and triggers them to destroy synapses between neurons.

Alzheimer's Fibrinogen Graphical Abstract
Source: Neuron

“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,” wrote the investigators.

“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.”

Previous studies have shown that elimination of synapses causes memory loss, a common feature in Alzheimer’s disease and other dementias. The researchers demonstrated that preventing fibrinogen from activating the brain’s immune cells protected mouse models of Alzheimer’s disease from memory loss.

“We found that blood leaks in the brain can cause elimination of neuronal connections that are important for memory functions,” explained Akassoglou, who is also a professor of neurology at University of California, San Francisco (UCSF). “This could change the way we think about the cause and possible cure of cognitive decline in Alzheimer’s disease and other neurological diseases.”

Fibrinogen that leaks from the blood into the brain activates the brain’s immune cells, triggering them to destroy the synapses between neurons. This effect, first observed at the Gladstone Institutes, resembles a form of degradation seen in Alzheimer’s disease, but it occurs even if amyloid plaque formation, a hallmark of Alzheimer’s, is absent. The implication is that protection against Alzheimer’s may require dual therapies.

The team showed that fibrinogen can have this effect even in brains that lack amyloid plaques, which are the focus of diverse treatment strategies that have failed in large clinical trials. They demonstrated that injecting even extremely small quantities of fibrinogen into a healthy brain caused the same kind of immune cell activation and loss of synapses they saw in Alzheimer’s disease.

“Traditionally, the build-up of amyloid plaques in the brain has been seen as the root of memory loss and cognitive decline in Alzheimer’s disease,” said Mario Merlini, PhD, first author of the study and a staff research scientist in Akassoglou’s laboratory at Gladstone. “Our work identifies an alternative culprit that could be responsible for the destruction of synapses.”

The scientists’ data could help explain findings from recent human studies in which elderly people with vascular pathology showed similar rates of cognitive decline as age-matched people with amyloid pathology. However, patients with both types of pathology had much worse and more rapid cognitive decline. Other studies also identified vascular pathology as a strong predictor of cognitive decline that can act independently of amyloid pathology.

“Given the human data showing that vascular changes are early and additive to amyloid, a conclusion from those studies is that vascular changes may have to be targeted with separate therapies if we want to ensure maximum protection against the destruction of neuronal connections that leads to cognitive decline,” said Akassoglou.

Akassoglou and her colleagues recently developed an antibody that blocks the interaction between fibrinogen and a molecule on the brain’s immune cells. In a previous study, they showed this antibody protected mouse models of Alzheimer’s disease from brain inflammation and neuronal damage.

“These exciting findings greatly advance our understanding of the contributions that vascular pathology and brain inflammation make to the progression of Alzheimer’s disease,” said Lennart Mucke, MD, co-author of the study and director of the Gladstone Institute of Neurological Disease. “The mechanisms our study identified may also be at work in a range of other diseases that combine leaks in the blood-brain barrier with neurological decline, including multiple sclerosis, traumatic brain injury, and chronic traumatic encephalopathy. It has far-reaching therapeutic implications.”

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