4:15 PM
Mar 01, 2018
 |  BC Innovations  |  Product R&D

Sigma for synapses

How Cognition plans to protect synapse function in AD via sigma-2

By focusing on synapse protection instead of aggregate formation, Cognition Therapeutics Inc. has identified a new target for Alzheimer’s disease that it believes can block β amyloid’s toxic effects more efficiently than the standard approaches. The idea is that targeting the relatively understudied σ-2 receptor could preserve -- and maybe regenerate -- synapses, halting or reversing cognitive decline.

While recent research in neuropsychiatric disorders has sought new targets related to synaptic connectivity and function, research in neurodegenerative disorders has largely focused on protein aggregation, and AD in particular has fixated on attacking β amyloid clusters or tau-filled neurofibrillary tangles.

In AD, monomers of the β amyloid peptide join together in the brain to form large extracellular clumps that are hallmarks of the disease, but smaller oligomeric forms of the peptide that remain soluble are thought to do the majority of the damage to neurons and synapses.

Cognition believes β amyloid oligomers drive synapse loss -- and ultimately memory failure -- by binding to neurons and inducing abnormal intracellular signaling. While there’s no consensus on the identity of the neuronal receptor for β amyloid oligomers, Cognition has data suggesting it belongs to a protein complex that interacts with the σ-2 receptor, a synaptic protein thus far studied primarily as a target in schizophrenia and cancer.

The company has shown that when its σ-2 antagonist CT1812 binds the receptor, it ejects the oligomer from the complex via an allosteric mechanism, preventing it from damaging the synapse (see “Bumped Out”).

Figure: Bumped out

Cognition Therapeutics Inc. is developing a σ-2 receptor antagonist CT1812 (Elayta) to protect neuronal synapses from the toxic effects of β amyloid oligomers in Alzheimer’s disease. Based on studies from its own and other labs, the company believes the σ-2 receptor is part of a multi-protein complex that modulates β amyloid oligomer (Aβ oligomer) binding on neuronal cell surfaces.

Top: The σ-2 receptor and the β amyloid oligomer receptor are indirectly connected via other members of their respective protein complexes. The full identity of the oligomer’s receptor isn’t known, but evidence in the literature suggests its protein complex could contain LILRB2 and PRNP.

Middle: In AD, β amyloid oligomers bind their receptor on neurons, triggering dysregulated neuronal signaling that ultimately leads to synapse loss.

Bottom: Cognition has shown its σ-2 receptor antagonist CT1812 (Elayta) increases the off-rate of β amyloid oligomer release from neurons, and has evidence suggesting the...

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