APOE ISOFORM-SPECIFIC EFFECTS ON AMYLOID-β-INDUCED PATHOLOGY: MICROGLIAL FUNCTION, NEURONAL INTEGRITY AND COGNITIVE DECLINE

Abstract

Although inheritance of APOE4 allele is a major genetic risk factor for late-onset Alzheimer's disease (AD), the mechanisms underlying this association remain elusive. APOE can differentially modulate amyloid β (Aβ) accumulation and clearance through blood brain barrier, or by astrocytic and microglial degradation. There are two conflicting views on how APOE4 impacts AD: APOE4 exhibits a loss of function, due to poor lipidation; or APOE4 particles are themselves toxic. There is increasing evidence that Aβ oligomers are the most toxic species, contributing to AD related cognitive decline and synaptic dysfunction. Microglia involvement in remodeling neuronal connectivity and maintaining brain homeostasis is achieved through their ability to rapidly interact to changes in the brain microenvironment, enabling adequate phenotypic transformations. Changes in microglia interfere with their supportive role in the brain, leading to synaptic dysfunction and consequent cognitive decline. We hypothesize that APOE interacts with Aβ in an isoform-dependent manner, thus affecting the formation of oligomeric Aβ species and consequently cognitive decline. Electron microscopy, Western blotting, and LC/MS were used to characterize APOE-Aβ complexes, resulting from co-incubating monomeric Aβ with APOE3 or APOE4 at oligomer forming conditions. We determined the ability of Aβ co-incubations to undergo phagocytosis in a primary microglial culture. We also determined the effects of Aβ co-incubations on synaptic and structural integrity in primary mouse neurons. We infused Aβ co-incubations into hippocampi of WT mice and examined cognitive performance. Lastly, following infusion of Aβ co-incubations into brains of WT mice we isolated both microglia and neurons and performed RNA-seq to determine transcriptome changes. We demonstrate that APOE3 and APOE4 particles have a unique phospholipid composition and both decrease Aβ oligomer formation, however to a different extent. APOE-Aβ complexes significantly impact neuronal structure and microglia phagocytosis. Hippocampal infusion of Aβ oligomers significantly decrease cognitive performance in association with significant changes if the transcriptome of microglia and neurons. This study demonstrates the isoform-dependent effect of APOE on the deleterious effect of oligomeric Aβ in AD related cognitive decline. Moreover, it provides further support to the concept that APOE is a potential therapeutic target for AD.