Engineering Proteins To Boost LTP And Memory

Synaptic plasticity (LTP) is considered the cellular correlate of learning and memory and its impairment has been linked to several neurological disorders, including Alzheimer's disease. Although the canonical pathways responsible for LTP involve dozens of proteins compartmentalized within dendritic spines, the LTP master controllers include key identified proteins such as CaMKII, LIMK1, PKC, BDNF and CREB. Using synthetic biology, we developed genetically encoded engineered proteins (GEEPs) to control their activity in living neurons boosting LTP. We employed artificial regulatory domains, whose conformations can be selectively and robustly controlled by the well-tolerated, clinically approved, blood-brain barrier permeant and procognitive drug rapamycin or its non-immunosuppressive analogs. Then, we combined biochemistry, electrophysiology, and two-photon imaging, demonstrating the viability of the proposed approach in controlling: •spine enlargement (GEE-LIMK1); •spine plasticity by either controlling BDNF maturation or engineering its receptor (GEE-BDNF/TrkB); •functional LTP (GEE-PKC) and •the clearance of misfolded proteins by engineering ADAM10. Using AAV infections and mouse behavioral analyses, we validated the potential of GEEPs to improve memory. Since several learning and memory disorders still lack efficacious treatments, our strategy will boost further research into next-generation bioengineering solutions as novel therapeutic strategies for in several brain disorders associated with cognitive dysfunctions.

Friday 03/03/2023 ore 12.00 AULA C CU010 - Prof. Cristian Ripoli Department of Neuroscience of Università Cattolica del Sacro Cuore– Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

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