Abstract

Apolipoprotein (apo) E4 is the leading genetic risk factor for Alzheimer’s disease (AD), and it has a gene dose-dependent effect on the risk and age of onset of AD. Although apoE4 is primarily produced by astrocytes in the brain, neurons can also produce apoE4 under stress conditions. ApoE4 is known to inhibit neurite outgrowth and spine development in vitro and in vivo, but the potential influence of apoE4’s cellular source on dendritic arborization and spine development has not yet been investigated. In this study, we report impairments in dendritic arborization and a loss of spines, especially thin (learning) and mushroom (memory) spines, in the hippocampus and entorhinal cortex of 19–21-month-old female neuron-specific-enolase (NSE)-apoE4 and apoE4-knockin (KI) mice compared to their respective apoE3-expressing counterparts. In general, NSE-apoE4 mice had more severe and widespread deficits in dendritic arborization as well as spine density and morphology than apoE4-KI mice. The loss of dendritic spines, especially mushroom spines, occurred in NSE-apoE4 mice as early as 7–8 months of age. In contrast, glial fibrillary acidic protein (GFAP)-apoE4 mice, which express apoE4 solely in astrocytes, did not have impairments in their dendrite arborization or spine density and morphology compared to GFAP-apoE3 mice at both ages. These results indicate that the effects of apoE4 on dendrite arborization, spine density, and spine morphology depend critically on its cellular source, with neuronal apoE4 having more detrimental effects than astrocytic apoE4.

Highlights

  • Apolipoprotein E is a 299-amino-acid glycoprotein that is highly expressed in the mammalian brain and occurs as three isoforms in humans–apoE2, apoE3, and apoE4

  • The Cellular Source of apoE4 Determines its Effects on Dendritic Arborization

  • We examined dendritic arborization in several apoE4 mouse models and their apoE3-expressing controls; namely: NSE-apoE4, apoE4-KI, and GFAPapoE4

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Summary

Introduction

Apolipoprotein (apo) E is a 299-amino-acid glycoprotein that is highly expressed in the mammalian brain and occurs as three isoforms in humans–apoE2, apoE3, and apoE4. These isoforms differ from each other by only one or two amino acid substitutions at positions 112 and 158, they have profound functional differences in relation to neurological disorders [1,2,3,4]. ApoE4-knockin (KI) mice, which express apoE4 under the control of an endogenous apoE promoter, are impaired in spatial learning and memory, albeit at an older age [17]. Mice whose apoE4 expression is limited to astrocytes do not show spatial learning and memory deficits, they do show impairments in working memory [18]

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