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

Abstract

Apolipoprotein receptor 2 (APOER2) is an alternatively spliced transmembrane receptor that binds the neuroprotective ligand Reelin and Alzheimers disease (AD) related risk factor, APOE. Splicing of single exons in mouse Apoer2 regulates 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 human APOER2 isoforms in the parietal cortex and hippocampus with 151 isoforms common between the two brain regions. In addition, we identified region- and AD-specific APOER2 isoforms suggesting APOER2 splicing is spatially regulated and altered in AD. We tested whether the AD-specific APOER2 transcripts 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.