The field of Alzheimer's research is undoubtedly undergoing a difficult time right now. Clinical trials are failing, big pharmaceutical companies are cutting research, and many scientists are suggesting the overriding causal hypothesis that has been driving most study for several decades could be wrong. Still, there are many exciting and new pathways being investigated, from the suggestion Alzheimer's could have a bacterial cause, to strong research finding sleep deprivation can hasten the onset of the disease.
Building on recent research finding associations between a breakdown in the blood-brain barrier and the onset of cognitive impairment, a new study has homed in on a specific blood-clotting protein that can trigger synaptic damage after leaking into the brain.
"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," explains Mario Merlini, first author of the study. "Our work identifies an alternative culprit that could be responsible for the destruction of synapses."
The new research reveals deposits of a protein called fibrinogen can be found in the brains of both human patients with Alzheimer's disease, as well as in experimental mouse models. It was discovered that when fibrinogen enters the brain through leaks in the blood-brain barrier, it activates an inflammatory response that causes damage to the synapses connecting individual neurons.
"We found that blood leaks in the brain can cause elimination of neuronal connections that are important for memory functions," says Katerina Akassoglou, senior investigator on the research.
Perhaps most interesting was the finding that fibrinogen can cause this synaptic damage in the absence of any amyloid plaque build-up. This implies the newly discovered process either precedes the toxic protein accumulation commonly associated with Alzheimer's, or is an entirely independent neurodegenerative mechanism. A subsequent animal study revealed administering small amounts of fibrinogen into a healthy brain resulted in synaptic damage very similar to what is seen in Alzheimer's disease.
This new study may offer a clue into how a permeable blood-brain barrier can trigger neurodegeneration. While a growing body of work is uncovering strong associations between blood-brain barrier breakdown and the earliest stages of cognitive decline, it is still unclear exactly what mechanism could be causing the damage.
There have been hypotheses put forward in the past suggesting an increasingly permeable blood-brain barrier may allow more toxic amyloid and tau proteins to enter the brain, kicking off the pathological process that leads to Alzheimer's. However, this new study suggests an alternative, and previously undiscovered process, may reveal an entirely separate neurodegenerative mechanism.
"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," says Akassoglou.
How this new discovery effectively translates into a human clinical treatment is yet to be determined. A previous study from the same research team demonstrated the development of a novel antibody that seems to effectively block the inflammatory activity of fibrinogen in the brain. In animal tests the antibody proved promising, decreasing brain inflammation and synaptic damage associated with the protein, but the treatment is still not ready for human testing. Akassoglou suggests that finding a treatment that safely disrupts this immune response and blood-clotting protein in humans without causing deleterious side effects will require cautious and careful research.
Still, this impressive work led by the Gladstone Institute of Neurological Disease, may have broad uses beyond just understanding Alzheimer's disease or dementia. This kind of synaptic damage associated with blood-brain barrier breakdowns could play a role in an assortment of different neurological conditions.
"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," says Lennart Mucke, co-author on the new study. "It has far-reaching therapeutic implications."
The new research was published in the journal Neuron.
Source: Gladstone Institutes
The field of Alzheimer's research is undoubtedly undergoing a difficult time right now. Clinical trials are failing, big pharmaceutical companies are cutting research, and many scientists are suggesting the overriding causal hypothesis that has been driving most study for several decades could be wrong. Still, there are many exciting and new pathways being investigated, from the suggestion Alzheimer's could have a bacterial cause, to strong research finding sleep deprivation can hasten the onset of the disease.
Building on recent research finding associations between a breakdown in the blood-brain barrier and the onset of cognitive impairment, a new study has homed in on a specific blood-clotting protein that can trigger synaptic damage after leaking into the brain.
"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," explains Mario Merlini, first author of the study. "Our work identifies an alternative culprit that could be responsible for the destruction of synapses."
The new research reveals deposits of a protein called fibrinogen can be found in the brains of both human patients with Alzheimer's disease, as well as in experimental mouse models. It was discovered that when fibrinogen enters the brain through leaks in the blood-brain barrier, it activates an inflammatory response that causes damage to the synapses connecting individual neurons.
"We found that blood leaks in the brain can cause elimination of neuronal connections that are important for memory functions," says Katerina Akassoglou, senior investigator on the research.
Perhaps most interesting was the finding that fibrinogen can cause this synaptic damage in the absence of any amyloid plaque build-up. This implies the newly discovered process either precedes the toxic protein accumulation commonly associated with Alzheimer's, or is an entirely independent neurodegenerative mechanism. A subsequent animal study revealed administering small amounts of fibrinogen into a healthy brain resulted in synaptic damage very similar to what is seen in Alzheimer's disease.
This new study may offer a clue into how a permeable blood-brain barrier can trigger neurodegeneration. While a growing body of work is uncovering strong associations between blood-brain barrier breakdown and the earliest stages of cognitive decline, it is still unclear exactly what mechanism could be causing the damage.
There have been hypotheses put forward in the past suggesting an increasingly permeable blood-brain barrier may allow more toxic amyloid and tau proteins to enter the brain, kicking off the pathological process that leads to Alzheimer's. However, this new study suggests an alternative, and previously undiscovered process, may reveal an entirely separate neurodegenerative mechanism.
"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," says Akassoglou.
How this new discovery effectively translates into a human clinical treatment is yet to be determined. A previous study from the same research team demonstrated the development of a novel antibody that seems to effectively block the inflammatory activity of fibrinogen in the brain. In animal tests the antibody proved promising, decreasing brain inflammation and synaptic damage associated with the protein, but the treatment is still not ready for human testing. Akassoglou suggests that finding a treatment that safely disrupts this immune response and blood-clotting protein in humans without causing deleterious side effects will require cautious and careful research.
Still, this impressive work led by the Gladstone Institute of Neurological Disease, may have broad uses beyond just understanding Alzheimer's disease or dementia. This kind of synaptic damage associated with blood-brain barrier breakdowns could play a role in an assortment of different neurological conditions.
"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," says Lennart Mucke, co-author on the new study. "It has far-reaching therapeutic implications."
The new research was published in the journal Neuron.
Source: Gladstone Institutes
