New Publication Identifies Key Proteins Involved in Amyloid Oligomer Binding and Supports Mechanism of CT1812
NEW YORK, Feb. 06, 2024 (GLOBE NEWSWIRE) -- Cognition Therapeutics, Inc. (NASDAQ: CGTX), a clinical stage company developing drugs that treat neurodegenerative disorders, announced that collaborators at the University of Edinburgh, Scotland published findings in the journal, Acta Neuropathologica, (doi: 10.1007/s00401-023-02679-6) that provide new insight into the biology of Alzheimer’s disease that is consistent with our understanding of the role the σ-2 receptor has in regulating Aβ oligomer binding.
Using a combination of two high-resolution microscopy techniques: array tomography and Förster resonance energy transfer (FRET), Professor Tara Spires-Jones and colleagues at the UK Dementia Research Institute at University of Edinburgh’s Centre for Discovery Brain Sciences analyzed protein-protein interactions in over 1 million individual synapses in brain samples from people who had died with Alzheimer’s disease. Results detected TMEM97, a protein component of the σ-2 receptor complex, in close proximity to cellular prion protein (PrPc) on Alzheimer’s brain synapses. In addition, results found that Aβ oligomers were proximate to both PrPc, which has been shown to bind Aβ oligomers in neuronal cultures, as well as to TMEM97. These findings support the hypothesis that these receptor proteins may form a complex on the synapse surface with Aβ oligomers binding to one or both proteins.
“Losing synaptic connections in the brain contributes to Alzheimer’s disease symptoms,” explained Professor Spires-Jones. “Previous work indicated that Aβ oligomers damage synapses, but until now it was not possible to know which proteins bind toxic forms of Aβ in human synapses. Combining FRET and array tomography imaging overcomes the limits of traditional microscopy and lets us determine whether proteins are close enough to interact in human brain samples. In simplest terms, while we had previous evidence that certain proteins existed in the same cellular neighborhood, we couldn’t precisely determine until now which houses were next to one another. Our findings help clarify the specific interactions between Aβ oligomers and synaptic receptors, which we hope will provide valuable information for drug developers.”
Professor Spires-Jones' work also confirmed that in the presence of CT1812, Cognition’s lead product candidate, Aβ oligomers are displaced from the oligomer receptor, a discovery echoed in the SNAP study, which was published in May 2023 in Translational Neurodegeneration. In Professor Spires-Jones' study using an Alzheimer's mouse model, a FRET signal was observed between TMEM97 and Aβ oligomers in synapses, which could occur if oligomers were bound to TMEM97 or to PrPc, the putative oligomer binding site. Importantly, this FRET signal is reduced in CT1812-treated mice, suggesting that CT1812 caused the release of Aβ oligomers from their binding site and prevented them from re-binding.
“Professor Spires-Jones' most recent work showing that CT1812 causes the removal of Aβ oligomers from synapses is an important confirmation of the mechanism initially proposed in the two seminal PLoS One papers authored by Cognition’s founding scientists,” explained Anthony Caggiano, MD, PhD, Cognition's CMO and head of R&D. "We believe these findings build on our clinical evidence that targeting the σ-2 receptor with CT1812 may offer a distinct and relevant new mechanism to fight Alzheimer’s disease progression by protecting synapses from the damaging effects of Aβ oligomers.”
About Cognition Therapeutics, Inc.
Cognition Therapeutics, Inc. is a clinical-stage biopharmaceutical company engaged in the discovery and development of innovative, small molecule therapeutics targeting age-related degenerative disorders of the central nervous system and retina. We are currently investigating our lead candidate CT1812 in clinical programs in Alzheimer’s disease, dementia with Lewy bodies (DLB) and dry age-related macular degeneration (dry AMD). We believe CT1812 and our pipeline of σ-2 receptor modulators can regulate pathways that are impaired in these diseases. We believe that targeting the σ-2 receptor with CT1812 represents a mechanism functionally distinct from other current approaches in clinical development for the treatment of degenerative diseases. More about Cognition Therapeutics and its pipeline can be found at https://cogrx.com.
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