Attacking Alzheimer's by protecting synapses from amyloid beta

The quest to clear damaging amyloid-beta plaques in the brain has long been the goal of Alzheimer's disease researchers and was the basis of the controversial FDA approval of Biogen's drug Aduhelm in early June. But University of California, San Diego (UCSD) neurobiologists believe taking a different route to combating amyloid beta—and the breakdown of synapses in the brain that it causes—may be a more effective weapon against the disease.

In mouse studies, the researchers discovered key components that lead to amyloid beta-associated synapse degeneration. They believe their discovery could inspire new approaches to the disease aimed protecting synapses via the direct blocking of amyloid beta's toxic actions. 

The research, published Wednesday in the journal Science Advances, focuses on glutamatergic synapses, which are critical to the ability of neurons to activate one another. The structures are formed by parts of a protein pathway. The UCSD scientists removed two components of that pathway, Celsr3 and Vangl2, causing the number of synapses to change. 

When the researchers removed Vangl2 from neurons, amyloid beta could no longer degrade synapses in cells or mouse models, they reported. They also blocked a regulator of the protein pathway called Ryk, which also seemed to protect the synapses from deterioration. 

This same pathway may be involved in the synapse loss associated with other neurodegenerative diseases, including Parkinson's and amyotrophic lateral sclerosis, said Yimin Zou, Ph.D., a UCSD professor and author on the study, in a statement

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The amyloid beta hypothesis of Alzheimer's persists, despite having led to 200-plus failed drug development programs. 

Denali Therapeutics and Washington University researchers reported in February that their anti-amyloid antibody, HAE-4, reduced the protein's toxic buildup in mice without triggering the brain bleeds that can come with the use of Aduhelm. Meanwhile, AbbVie is moving its own beta amyloid candidate into the clinic in the coming months, the company said in late July. 

UCSD's Zou believes the signaling proteins at the heart of the new study may be the "Achilles’ heel of our synapses," he said in the statement. “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 that pathway could be a viable treatment strategy, he said.