A Mechanism by which Amyloid-β Can Cause Degeneration of Synapses
Misfolding and aggregation of amyloid-β in the brain is thought to be the initial cause of mild cognitive impairment that leads into Alzheimer's disease. In recent years, this hypothesis has been challenged as clearance of aggregates via immunotherapy has failed to produce improvements in patient outcomes. This may be because the extracellular aggregates are a side-effect and the real harms conducted by amyloid-β occur elsewhere, inside cells. Or it may be that amyloid-β aggregation is a side effect, and other mechanisms such as chronic inflammation and chronic infection are the real drivers of Alzheimer's disease. Nonetheless, mechanistic evidence continues to link amyloid-β with pathology, such as the degeneration of synapses.
In brain disorders such as Alzheimer's, synaptic connections, which hold our precious memories, are known to break down too early and disappear. This synapse degeneration is thought to start long before the loss of memory and accelerate as diseases progress. The causes of synapse degeneration in neurodegenerative disorders has not been well understood, mainly because scientists have not yet unraveled the key mechanisms that normally hold together these tiny structures. Researchers have now identified the main components driving amyloid beta-associated synapse degeneration. Amyloid beta are peptides of 36-43 amino acids derived from the amyloid precursor protein (APP) and are the main component of amyloid plaques found in the brains of people with Alzheimer's disease.
Glutamatergic synapses are highly polarized structures with a presynaptic part from one nerve cell and a postsynaptic part from another. This type of polarity ensures the proper direction of information flow. Researchers had previously found that during brain development the highly polarized synaptic structures are assembled by components of the planar cell polarity (PCP) pathway: a powerful signaling pathway that polarizes cell-cell junctions along the tissue plane. Using super resolution microscopy, the researchers detected the precise location of these same PCP signaling components, called Celsr3, Frizzled3, and Vangl2, in the glutamatergic synapses in the adult brain. They then found that removing these components, essential for the initial assembly of synapses from adult neurons, can dramatically alter the number of synapses. These surprising discoveries suggest that the overall synapse number in a normal brain is maintained by a fine balance between Celsr3 (which stabilizes synapse) and Vangl2 (which disassembles synapses).
Curious about whether these components are involved in synapse degeneration, reserachers tested whether amyloid beta, a key driver of synapse loss in Alzheimer's disease, affects the function or interaction of these proteins. In a series of experiments, they showed that amyloid beta oligomers bind to Celsr3 and allow Vangl2 to more effectively disassemble synapses, likely by weakening the interactions between Celsr3 and Frizzled3. Ryk, a regulator of the PCP pathway that interacts with Frizzled3 and Vangl2, is also found present in the adult synapses and functions in the same way as Vangl2 to mediate synapse disassembly. Blocking Ryk using function-blocking antibodies can protect synapses from amyloid beta-induced degeneration.
The researchers then used 5XFAD mice, a well-known mouse model of amyloid beta pathology. This transgenic mouse carries five human mutations that cause Alzheimer's disease and therefore shows severe symptoms of synapse degeneration and cognitive function loss. They found that removing Ryk by gene knockout from adult neurons protected synapses and preserved cognitive function of 5XFAD mice. Infusion of the function blocking the Ryk antibody also protected synapses and preserved cognitive function in 5XFAD mice, suggesting the Ryk antibody is a potential therapeutic agent.