Brain transcriptomic and proteomic analyses in an in vivo AD model further elucidate the role of the sigma‐2 receptor modulator CT1812 in Alzheimer’s disease
Valentina Di Caro, Eunah Cho, Jill Caldwell, Kiran Pandey, Duc M. Duong, Nicholas T Seyfried, Anthony O Caggiano, Mary E Hamby- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
CT1812 is a first in class small molecule sigma‐2 receptor (S2R) modulator, currently in Phase II clinical trials for Alzheimer’s disease (AD), that selectively displaces Aβ oligomers from synapses. CT1812 prevents synaptotoxicity and restores cognitive performance in a transgenic mouse model of AD. To better understand and identify the biological process that S2R modulator can impact, we performed transcriptomic and proteomic analysis in brain from an in vivo mouse model of AD treated with our leading investigational therapeutic CT1812.
Method
Non‐transgenic or transgenic AD (hAPPsl) mice were dosed with vehicle and/or CT1812 (10 mg/kg, given orally, once daily) for 7 days. Animals were sacrificed 24 hr after last dose, and brain collected. Unbiased RNA‐Sequencing and tandem‐mass tag mass spectrometry (TMT‐MS) proteomic measurements and analyses were performed of mouse hippocampus (N = 10 per group) to evaluate differential expression between transgenic and non‐transgenic mice, and to assess effect of CT1812 compared to vehicle. STRING and MetaCore pathway analyses were performed on both RNA‐Seq and proteomics analysis using gene lists of P ≤ 0.05.
Result
For the first‐time the hAPPsl mouse model has been characterized at both transcriptomic and proteomic level, and data indicate that specific aspects of AD are recapitulated in this model, e.g. APP is the most upregulated protein (p<0.05). In the brain, treatment with CT1812 altered the expression level of protein and mRNA (219 proteins and 2,031 mRNA transcripts were changed (p ≤ 0.05)). Pathway analysis by STRING and MetaCore (p<0.05) indicated a role of CT1812 in altering key pathways including membrane trafficking, autophagy, inflammation, cytoskeleton remodeling and WNT/β‐catenin signaling. Comparative analysis of the differentially expressed proteins between the proteomic and RNA‐Seq highlights 36 proteins that may be regulated transcriptionally, including Rab8b, Lamtor3, and Opa1, all which are associated with AD phenotype.
Conclusion
Our RNA‐Seq and proteomic analysis data have demonstrated that S2R modulators can impact the neuron function at a molecular level. These new findings help elucidate the molecular mechanism of action CT1812 in Alzheimer’s disease.