Heterogeneity of novel APOER2 isoforms specific to Alzheimer’s disease impact cellular and synaptic states

Abstract

SUMMARYApolipoprotein receptor 2 (APOER2) is an alternatively spliced transmembrane receptor that binds the neuroprotective ligand Reelin and Alzheimer’s disease (AD) related risk factor, APOE. Splicing of single exons in mouseApoer2regulates neuronal function and synaptic plasticity. However, the splicing landscape and function of human APOER2 isoforms in physiological and AD conditions remains unclear. Here, we identified over 200 unique humanAPOER2isoforms in the parietal cortex and hippocampus with 151 isoforms common between the two brain regions. In addition, we identified region- and AD-specificAPOER2isoforms suggestingAPOER2splicing is spatially regulated and altered in AD. We tested whether the AD-specificAPOER2transcripts have distinct functional properties, and demonstrated AD-specific APOER2 variants have altered cell surface expression, APOE-mediated receptor processing and synaptic changes which could contribute to neuronal dysfunction associated with AD pathogenesis.