Apoe and reelin interactions in alzheimer's disease

The National Institute on Aging awarded Rensselaer Polytechnic Institute $698,712 on September 1, 2026, under the Aging Research program (CFDA 93.866) to investigate apolipoprotein E and reelin interactions in Alzheimer's disease pathology.

The research tests the hypothesis that APOE E4 competes with reelin for receptor and heparan sulfate binding, thereby reducing protective reelin signaling and increasing Alzheimer's disease risk. Work includes mechanistic studies using split luciferase assays and iPSC-derived APOE E44 organoids to measure reelin's capacity to reduce tau phosphorylation and neurofilament light chain secretion as a biomarker of neurodegeneration. The project also characterizes the RELN-COLBOS H3447R variant's increased affinity for heparan sulfate and its enhancement of downstream DAB1 signaling relative to wild-type reelin, with particular focus on how reelin-DAB1 signaling modifies Alzheimer's disease risk in APOE E4 individuals through the proposed pathway: reelin–APOER2/VLDLR/heparan sulfate–DAB1–GSK3B–phosphorylated tau, resulting in reduced tau phosphorylation and aggregation.

Performance occurs in Troy, New York, with a period of performance from September 1, 2026, through August 31, 2027. This is a Project Grant, a competitive award type supporting discrete, time-limited research projects within the National Institute on Aging's mission to support research directed toward understanding aging processes and preventing Alzheimer's disease and related dementias.

Abstract

Apoe Ε4, which encodes apolipoprotein e protein (apoe) Ε4, is the strongest genetic risk factor for late-onset alzheimer's disease. In the brain, apoe is synthesized and lipidated by astrocytes and then secreted to shuttle cholesterol to neurons. Apoe binds to receptors on the neuron surface, including APOER2 (LRP8) and vldlr, as well as heparan sulfate (HS). LRP8, vldlr, and HS all bind another secreted protein, reelin (encoded by the reln gene), which plays fundamental roles in brain development and synaptic plasticity. Intriguingly, recent advances indicate that reelin signaling is a protective pathway against neurodegeneration. For example, the rare reln-colbos variant may protect from the PSEN1 E280A mutation. This charge-increasing variant H3447R has increased affinity for HS and can increase downstream DAB1 signaling compared with wild-type (WT) reelin. Single-nucleus transcriptomics has revealed the loss of reln+ neurons in the entorhinal cortex in ad patients, reducing this potentially protective molecule. Notably, reelin-DAB1 signaling modifies alzheimer's disease risk in apoe Ε44 individuals. Reelin protection has been proposed to act through the pathway: reelin- APOER2/vldlr/HS-DAB1-GSK3B-ptau, resulting in reduced TAU phosphorylation and aggregation. In our preliminary studies using a split luciferase assay, we found that apoe Ε4 inhibits reelin activation while apoe Ε3 has little effect. Furthermore, in ipsc-derived apoe Ε44 organoids, we found that exogenous reelin protein can reduce TAU phosphorylation and neurofilament light chain (NFL) secretion, a biomarker of neurodegeneration. These exciting data, coupled with fact that reelin and apoe bind to the same receptors, have led US to the overarching hypothesis that apoe Ε4 competes with reelin for receptor and HS binding, thereby reducing protective reelin signaling and increasing alzheimer's disease risk. We will test this overarching hypothesis with a multi-scale, interdisciplinary approach, with three specific aims: 1) study reln+ cell association with apoe Ε4 and ad pathology in ad brains; 2) characterize the impact of reelin on ad molecular signatures, comparing apoe Ε44 VS apoe Ε33 in 3D brain organoids with isogenic background; 3) define the molecular mechanisms of how apoe Ε4 diminishes reelin signaling. Successful completion of the proposed project will offer insights into how apoe Ε4 increases alzheimer's disease risk via interactions with the reelin signaling pathway and has the potential to identify novel approaches to counteract apoe Ε4, which is present in approximately half of alzheimer's disease patients.