Scientists believe one of the key culprits behind the cognitive decline seen in Alzheimer's are amyloid beta proteins that clump together and disrupt the brain's synaptic connections, but how they carry out such degeneration has remained unclear. A new study has shone compelling new light on this phenomenon, with the authors demonstrating how these toxic agents take aim at the "Achilles' heel" of synapses, and better yet, how they might just be stopped.
The toxic brain plaques made up of amyloid beta proteins are considered a key driver of Alzheimer's and similar neurological conditions, as they aggregate at the synapses to interfere in the signals they relay between nerve cells, disrupting thought, memory and other cognitive functions. A lot of research focuses on ways to prevent them building up or developing drugs to bust them apart, but the authors of this new study have taken a slightly different approach, by digging into the details behind synaptic degeneration.
Neurobiologists at the University of California (UC) San Diego focused on a major type of synapse called glutamatergic synapses. During brain development, these synapses are pieced together by a powerful signaling pathway called the planar cell polarity (PCP) pathway, which includes signaling components called Celsr3 and Vangl2. These work in harmony to stabilize and disassemble synapses, respectively, to keep their numbers at a healthy level.
The scientists explored how these roles might be influenced by the presence of amyloid beta, and carried out experiments in culture and on mouse models of Alzheimers's showing how the amyloid beta oligomers actually bind to Celsr3. This clears the way for Vangl2 to more readily disassemble synapses, with the subsequent removal of Vangl2 from the neurons proving to rob amyloid beta of its ability to destroy synapses.
“This is as if amyloid beta has long discovered the Achilles’ heel of our synapses,” says study author Professor Yimin Zou.
The researchers then turned their attention to another key component of the PCP pathway called Ryk, which functions much like Vangl2 in mediating synapse disassembly. Using special antibodies, the scientists blocked the function of Ryk and found that this too prevented the degeneration of synapses by the amyloid beta proteins. In mouse models of Alzheimer's, both knocking out the gene for Ryk and administering the Ryk-blocking antibody protected the synapses and preserved cognitive function.
“As amyloid beta pathology and synapse loss usually occurs in early stages of Alzheimer’s disease, even before cognitive decline can be detected, early intervention, such as restoring the rebalance of the PCP pathway, will likely be beneficial for Alzheimer’s patients,” says Zou.
The Ryk antibody also proved effective at quelling some of the signs of neuroinflammation seen in Alzheimer’s, though the exact mechanisms behind this are unclear. In any case, the scientists believe these results indicate the PCP could prove a valuable target in efforts to protect synapse loss in Alzheimer's disease, and potentially other conditions.
“This discovery may be applicable to synapse degeneration in general as the PCP components may be the direct synaptic targets mediating synapse loss in other neurodegenerative disorders, such as Parkinson’s disease and Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease),” says Zou.
The research was published in the journal Science Advances.
Source: UC San Diego
