It is still unclear exactly what causes Alzheimer’s disease, which is a neurodegenerative condition chiefly characterized by memory loss and other forms of cognitive impairment. However, new research is uncovering more of the factors that contribute to its pathology.
These are buildups of toxic proteins that disrupt the normal functioning of synapses. Synapses are the connections formed between brain cells that allow information to circulate within and to and from the brain.
However, in a new study from the Gladstone Institutes in San Francisco, CA, a team of researchers has identified another mechanism that affects how synapses work, contributing to Alzheimer’s pathology.
The researchers began by investigating problems that appear in the blood vessel network in the brain, which is another biological characteristic of this form of dementia.
Senior investigator Prof. Katerina Akassoglou and her team have for the first time identified a blood-derived protein that leaks into the brain disrupting cell-to-cell communication.
In this study, the investigators used sophisticated imaging technology to scan both the brains of mice simulating a form of dementia and those of people with an Alzheimer’s diagnosis.
Through their analyses, the researchers found that fibrinogen passes from blood vessels into the brain, triggering immune cell activity, which in turn leads to the breakdown of synapses.
To confirm the protein’s role in synaptic breakdown, the team tried blocking fibrinogen’s action on the brain’s immune cells in a mouse model of Alzheimer’s. This strategy protected the rodents from experiencing the type of memory loss typically associated with this condition.
“We found that blood leaks in the brain can cause elimination of neuronal connections that are important for memory functions. This could change the way we think about the cause and possible cure of cognitive decline in Alzheimer’s disease and other neurological diseases.”
Prof. Katerina Akassoglou
Moreover, Prof. Akassoglou and her team found that leaked fibrinogen can lead to synaptic breakdown even in the absence of beta-amyloid plaques.
When the researchers injected even the smallest of quantities of fibrinogen into healthy brains, they saw that the protein triggered the same mechanism that caused the loss of synapses as it did in brains affected by Alzheimer’s disease.
“Traditionally, the buildup of amyloid plaques in the brain has been seen as the root of memory loss and cognitive decline in Alzheimer’s disease,” explains the study’s first author, Mario Merlini.
“Our work identifies an alternative culprit that could be responsible for the destruction of synapses,” he notes.
The team that conducted the current study explains that existing research has shown that cerebrovascular problems, as well as the formation of beta-amyloid plaques, each
Moreover, both of these pathologies contribute to the cognitive decline at similar rates. However, the researchers add that people who present both pathologies at the same time experience much quicker neurodegeneration.
Prof. Akassoglou and colleagues believe that their current findings finally offer an explanation for these phenomena.
“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,” notes the senior researcher.
So far, researchers have been developing therapies targeting beta-amyloid, but these new findings suggest that other therapeutic targets may also be valuable.
“These exciting findings greatly advance our understanding of the contributions that vascular pathology and brain inflammation make to the progression of Alzheimer’s disease,” says study co-author Dr. Lennart Mucke.
“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,” he adds.