Isoform-specific effects of human apolipoprotein E on brain function revealed in <i>ApoE</i> knockout mice: Increased susceptibility of females

TLDR

Apolipoprotein E mediates lipid redistribution, is highly expressed in brain and liver, exists in three isoforms (ɛ2, ɛ3, ɛ4), with ɛ4 increasing risk of cognitive impairment and earlier onset of Alzheimer’s disease, and is the most important known risk factor for sporadic AD, yet how it affects cognition remains unclear. The study aims to assess the effects of distinct human apoE isoforms on brain function and to facilitate preclinical evaluation of treatments for apoE‑related cognitive deficits. Using the neuron‑specific enolase promoter, the authors expressed human apoE3 or apoE4 at comparable levels in neurons of apoE‑knockout mice. NSE‑apoE4 mice displayed age‑dependent learning impairments and reduced vertical exploratory behavior, primarily in females, indicating isoform‑specific deficits that may underlie cognitive impairments seen in human APOE ɛ4 carriers.

Abstract

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (ɛ 2 , ɛ 3 , and ɛ 4 ). Compared with APOE ɛ 2 and ɛ 3 , APOE ɛ 4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer’s disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE ɛ 4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE ɛ 4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE ɛ 4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.