NIH Research Festival
The number of Americans with Alzheimer’s disease (AD) is projected to increase by almost 40% by the year 2025, and so far there are no effective treatments. Neurons in the entorhinal cortex that express the secreted protein reelin and project their axons to the hippocampus degenerate very early in the disease process, and downregulation of reelin expression precedes their demise. Reelin plays a pivotal role not only in regulating the laminar organizations during brain development but also in adult neurogenesis. The latter is thought to occur by controlling the migration of neural precursor cells (NSC) in the subgranular layer of the dentate gyrus of the hippocampus. We discovered a nontelomeric isoform of TRF2 (TRF2-S) that is coexpressed with reelin in Cajal-Retziuz neurons in embryonic cortical brain and in is present in the exosomes released from cultured cortical neurons. TRF2-S knockdown in neuron cultures and in hippocampus in vivo reduces the expression of full-length reelin protein and affects the memory for extinction of conditioned fear, respectively. Conversely, TRF2-S elevation promotes neuronal differentiation and prevents excitotoxic neuronal cell death. In the current studies we are testing the hypothesis that elevation of TRF2-S levels via lentivirus or delivery of exosomes in NSCs in culture will have neuroprotective and neurogenesis-promoting actions in cell culture and animal models of AD. We will determine whether downregulation of reelin by amyloid beta-peptide can be reversed by TRF2-S. These studies may reveal a novel approach for preserving the entorhinal cortex – hippocampal circuit that affected early in AD.
Scientific Focus Area: Neuroscience
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