Although we do not yet fully understand the pathophysiological mechanisms of Alzheimer’s disease, we know that it is linked, among other things, to an abnormal accumulation of amyloid plaques in the brain, according to the famous theory of the “amyloid cascade”. . However, the lack of efficacy of current treatments seems to cast doubt on this hypothesis, and further increases the need for research into new therapeutic targets. Several studies believe that this problem of effectiveness is due in particular to the impermeability of the blood-brain barrier. A new study published in the journal Molecular Psychiatry suggests going through another route: total blood exchange. This “replacement” of blood would have made it possible to reduce the formation of amyloid plaques in the brains of sick mice, by preventing defects in protein folding in the bloodstream.
The neurological changes caused by Alzheimer’s disease generally result in alterations in synaptic communication, cerebral inflammation, the aggregation of the famous amyloid plaques, neurofibrillary entanglement and the accelerated end of life of neurons.
According to the amyloid cascade theory, the protein would accumulate in the form of dense plaques, hindering interneuronal or synaptic communication. These aggregates then disperse to end up accumulating in the hippocampus (responsible for memory) and causing symptoms of dementia. Over time, the blockage caused by the amyloid plaques leads to the death of neurons and the atrophy of key areas in the brain, worsening the symptoms of the disease.
On the other hand, tau entanglement is also thought to be implicated in dementia symptoms. This protein in the form of rectilinear “rails” is notably responsible for the supply of nutrients and the transmission of neurotransmitters at the level of neurons. In a diseased brain, its structure twists and collapses, causing the formation of fibrillar clusters (neurofibrillar tangles) of tau proteins and eventually suffocating and killing adjacent neurons.
In both cases, the folding defects of the proteins upstream would be responsible for their dysfunction and their abnormal aggregation. Folding is indeed the key molecular mechanism by which the polypeptide chains carrying genetic information wind up between themselves to form a three-dimensional structure. The latter is essential for the expression of downstream molecular functions and mechanisms.
At the moment, most of the treatments available for Alzheimer’s disease focus mainly on the elimination of amyloid plaques. However, most therapeutic molecules are “filtered” by the blood-brain barrier, and only a small percentage actually reach their destination (at the level of neurons).
Bypass the blood-brain barrier
In the new study conducted by the University of Texas Health (UTHealth Houston), researchers want to target protein folding directly at the level of the bloodstream. This strategy would make it possible in particular to prevent the aggregation of amyloid plaques while avoiding the molecular barrier that the blood-brain barrier might constitute.
« The blood vessels in the brain are classically considered the most impermeable barrier in the body “, explains in a communiqué Akihiko Urayama, associate professor at UT Health in Houston and co-lead author of the new study. ” We found that this barrier is at the same time a very specialized interface between the brain and the systemic circulation. “, he adds.
According to the researchers, patients, whose blood is loaded with amyloid plaque precursor proteins, might be “cleansed” of these pathological factors by completely replacing their blood (composed of erythrocytes, leukocytes, platelets and plasma) by transfusion from a healthy donor, similar to plasmapheresis or dialysis. The advantage of this new approach would be to be able to circumvent the “barrier effect” of the blood-brain membrane, by using existing technologies.
As part of their study, the authors performed a series of treatments on diseased mouse models, partially replacing their blood with that of healthy mice of the same genetic line. After several transfusions, the researchers observed a 40 to 80% decrease in amyloid plaques in mice in which an experimental form of Alzheimer’s disease had been induced. In addition, this reduction of plaques would have improved spatial memory in sick and old mice, while slowing down their accumulation over time.
However, the solution may not be so simple, and the mechanisms by which blood exchange can potentially reduce plaque buildup may differ in humans. More research will therefore be needed to shed light on these mechanisms. Moreover, although a blood treatment for Alzheimer’s would perhaps be a major advance, it must be taken into account that blood exchange treatments are often invasive and exhausting for patients.
