ApoE Regulates Corticospinal Neuronal Survival Through ApoER2

Abstract

This study was designed to characterize the role of ApoER2 and its ligand ApoE in the regulation of neuronal survival of normally aging CSN and after axonal injury. We also investigated, which of the intracellular domain of ApoER2 initiate the signal transduction and mediates survival or neuronal death. To this end, we used an experimental model in genetically altered ApoER2 and in ApoE−/− mouse strains using a stereological approach. To determine the role of ApoE and ApoER2 in neuronal survival in vivo, we used retrograde fluorescent-dye labeling of corticospinal neurons to monitor neuronal loss during aging or after injury by deafferation. Quantitation of corticospinal neuron numbers were determined with a stereological approach in which the total number of CSN in the entire cortex was assessed.

Our data indicate that ApoE, similar to ApoER2, promotes the survival of intact mature neurons while it induces their death after lesion. To our knowledge, ApoE/ApoER2 is so far the only ligand/receptor system described to promote the survival of intact mature CNS neurons in vivo. Our work also implies that ApoER2 promotes CSN survival via its alternatively spliced exon 19, and that separate receptor domains of ApoER2 regulate neuronal migration and survival.

The similar patterns of ApoE and ApoER2 on survival regulation suggest that ApoE and ApoER2 act in concert, possibly as a ligand/receptor pair, in the regulation of neuronal survival in vivo. Our results might be important for the understanding of neuronal death in the context of neurodegenerative diseases.