Cognitive enhancers

We study molecular and cellular mechanisms underlying learning and memory, and recently, depression as well. Since the foundation of the lab, we have been studying the regulation of mRNA translation into protein as a major molecular mechanism underlying memory consolidation. Over the years, we have focused on specific pathways that serve as key regulators of protein synthesis, and shown them to be potential targets for memory enhancement in health and disease (e.g., mild dementia, Alzheimer’s disease). We have shown that eIF2α and at least two of its kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), play an essential role in learning and memory. Moreover, phosphorylation of eIF2α is increased with age in rats and mice, and in the ApoE4 mouse model of sporadic Alzheimer’s disease, phosphorylation levels of PKR and eIF2α are increased (Segev et al. 2013), and PKR inhibition rescues memory impairment, as shown in the contextual fear conditioning paradigm (hippocampal-dependent) (Segev et al. 2015). Our findings regarding PKR, as a potential target for memory enhancement in health and disease, have been granted a patent. Based on our findings regarding PKR and this patent, in 2015 we founded a start-up company (Protekt Therapeutics, part of the FuturX biotechnological incubator, Israel) aiming to develop PKR inhibitors, invested by Takeda Pharmaceuticals and Johnson & Johnson. Recently, together with Professor Sonenberg group in McGill, Montreal, we identify the neuronal types where memory consolidation takes place.

 

Relevant recent references on the subject:

 

eIF2α pathway controls memory consolidation via excitatory and somatostatin inhibitory neurons (2020). Vijendra Sharma…Kobi Rosenblum and Nahum Sonenberg. Nature. 2020 Oct 7. doi: 10.1038/s41586-020-2805-8.

 

Adaikkan C, Taha E, Barrera I, David O, Rosenblum K (2018). Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine. Biol Psychiatry. 84(1):65-75.

 

Sharma V, Ounallah-Saad H, Chakraborty D, Hleihil M, Sood R, Barrera I, Edry E, Kolatt Chandran S, Ben Tabou de Leon S, Kaphzan H, Rosenblum K (2018). Local Inhibition of PERK Enhances Memory and Reverses Age-Related Deterioration of Cognitive and Neuronal Properties. J Neurosci. 38(3):648-658.

 

Segev Y, Michaelson DM, Rosenblum K. 2013. ApoE epsilon4 is associated with eIF2alpha phosphorylation and impaired learning in young mice. Neurobiol Aging 34: 863-872.

 

Segev Y, Barrera I, Ounallah-Saad H, Wibrand K, Sporild I, Livne A, Rosenberg T, David O, Mints M, Bramham CR, Rosenblum K. 2015. PKR inhibition rescues memory deficit and ATF4 overexpression in ApoE epsilon4 human replacement mice. J Neurosci 35: 12986-12993.

 

Stern E, Chinnakkaruppan A, David O, Sonenberg N, Rosenblum K. 2013. Blocking the eIF2alpha kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory. J Neurosci 33: 2517-2525.