Protein Expression of Alzheimer's disease‐ and Reduced Hippocampal Volume‐ Risk Loci in Human Hippocampus

Abstract

We examined the protein expression of novel genome‐wide association studies (GWAS) identified risk alleles implicated in Alzheimer's disease (AD) and low hippocampal volume using postmortem hippocampi with no or mild‐to‐moderate AD‐associated pathological changes. We found BIN1, the most significant late‐onset AD susceptibility locus after APOE, expressed in glia of all the examined cases while the punctate signal in neuropil varied substantially. EPHA1, another confirmed AD risk locus, is an ephrin receptor implicated in neuronal apoptosis. We found EphA1 in the neuronal cytoplasm, with a trend of decreasing signal intensity as AD progressed. Methionine sulfoxide reductase B3 (MSRB3) locus, critical for oxidative stress, was identified in GWAS on hippocampal volume. We found MSRB3 signal mostly as cytoplasmic puncta in pyramidal neurons from all of the examined cases, albeit in various amounts. Finally, LEMD3, a possible causal gene at the MSRB3 locus, was expressed in neurons as well as astrocytes. Neuronal expression of LEMD3 may increase with AD progression. Our data provide first insight into the human hippocampal cell type‐ and cell compartment‐specific protein expression of AD‐ and hippocampal volume reduction‐ risk alleles. We are currently examining the correlation of these proteins' expression with the cognitive status reflected in CDR (Clinical Dementia Rating) scores.