ALTERATIONS IN APOLIPOPROTEIN E EXPRESSION DURING AGING AND NEURODEGENERATION

doi:10.1016/S0301-0082(96)00038-X

Progress in Neurobiology

Volume 50, Issues 5–6, December 1996, Pages 493-503

https://doi.org/10.1016/S0301-0082(96)00038-X Get rights and content

Abstract

Apolipoprotein E (apoE) is a 34 kDa protein that plays an important role in cholesterol transport, uptake and redistribution. Within the nervous system, apoE might be involved in maintaining synaptic integrity after injury and during aging. ApoE might help maintain the integrity of the synaptodendritic complex by several different mechanisms. Among them, recent studies have suggested that apoE: (1) stabilizes the neuronal cytoskeleton; (2) plays an important role in transporting esterified cholesterol to neurons undergoing reinnervation where it is taken up by the low density lipoprotein receptor-related protein pathway and used as a precursor for the synthesis of new synaptic terminals; (3) regulates interactions between neurons and the extracellular matrix (e.g. laminin); and (4) regulates levels of intracellular calcium. The main objective of the manuscript is to review the current progress in understanding the functions of apoE in the nervous system and how malfunctioning of this molecule might result in neurodegenerative disorders such as Alzheimer's disease. Copyright © 1996 Elsevier Science Ltd.

Section snippets

INTRODUCTION

Neuronal maintenance during aging and after central nervous system (CNS) injury requires the concerted action of several cellular factors that will help to: (a) stabilize intracellular calcium levels (Iacopino and Christakos, 1990; Mattson et al., 1993; Michaelis et al., 1992); (b) clear excitotoxins and oxygen radicals from the synaptic cleft (Balcar and Li, 1992; Greenamyre and Porter, 1994; Kanai et al. (1993), Kanai et al. (1994)); (c) remodel protoplasmic and endomembrane structure; (d)

EXPRESSION OF APOE IN THE CNS DURING DEVELOPMENT AND AGING

Apolipoprotein E is a 34 kDa protein that plays and important role in cholesterol transport, uptake and redistribution (Mahley and Innerarity, 1983; Paik et al., 1985). ApoE is encoded by a polymorphic gene located in chromosome 19 (Lin-Lee et al., 1985) and the three different isoforms are coded by three separate alleles (ϵ2, ϵ3, ϵ4) that are inherited in a co-dominant fashion at a single genetic locus (Zannis and Breslow, 1981). ApoE mRNA is most abundant in the liver, followed by the

EXPRESSION OF APOE AFTER NERVOUS SYSTEM INJURY

Non-esterified cholesterol released after injury is esterified and transported by apoE to neurons undergoing reinnervation and taken up through the LDL-receptor (LDL-R) pathway where it is used as a precursor for the synthesis of new synaptic terminals (Poirier et al., 1993; Poirier, 1994). Furthermore, the LDL-R is present at high concentrations in regenerating peripheral nerve processes (Boyles et al., 1990), suggesting that apoE mediates the delivery of lipids to regenerating axons (

EXPRESSION OF APOE IN ALZHEIMER'S DISEASE (AD)

In AD, there is an extensive neuronal and synaptic loss in the limbic system and neocortex, accompanied by amyloid deposition and tangle formation (for review, see Terry et al., 1994). Taken together these findings, in conjunction with recent studies showing that approximately 64% of AD cases are associated with the presence of allele ϵ4 of APOE (Saunders et al., 1993), suggest that an abnormally functioning apoE, in addition to contributing to amyloid deposition and tangle formation (Benzing

CONCLUSIONS

The discovery of a role of apoE in pathogenesis of AD has helped to expand the effort toward understanding the central function of apoE in the CNS. These results are consistent with previous studies that have indicated a possible role for apoE in the plasticity of the CNS (Boyles et al., 1990; Handelmann et al., 1992; Poirier et al., 1991, Poirier et al., 1993; Poirier, 1994), suggesting that apoE might be critical in maintaining the integrity of the CNS during aging and after lesions (Masliah

Acknowledgements

The authors would like to thank Drs Breslow, Palinsky and Steinberg for providing the mice necessary for the present study, and Drs Katzman, Thal, Saitoh and Roses for their continued support and encouragement. This work was supported by grants AG05131 and AG10689, as well as with funding from the Alzheimer's Disease and Related Disorders Association and the Ruth K. Broad Research Foundation. This work also was supported partially by NIH grant RR04050.

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ALTERATIONS IN APOLIPOPROTEIN E EXPRESSION DURING AGING AND NEURODEGENERATION

Abstract

Section snippets

INTRODUCTION

EXPRESSION OF APOE IN THE CNS DURING DEVELOPMENT AND AGING

EXPRESSION OF APOE AFTER NERVOUS SYSTEM INJURY

EXPRESSION OF APOE IN ALZHEIMER'S DISEASE (AD)

CONCLUSIONS

Acknowledgements

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Mol. Brain Res.

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Neurosci. Lett

Neurosci. Lett.

Trends Neurosci.

Neurosci. Lett.

Expl Neurol.

J. Lipid Res.

Biochem. Biophys. Res. Commun.

Neurosci. Lett.

Expl Neurol.

J. Biol. Chem.

Cell

J. Lipid Res.

Biochim. Biophys. Acta

Expl Neurol.

Expl Neurol.

Brain Res.

Neuron

Mech. Ageing Dev.

Brain Res.

Brain Res.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

Molec. Brain Res.

Neuroscience

Trends Neurosci.

Neurosci. Lett.

Neuroscience

Expl Neurol.

Brain Res.

J. Neurol. Sci.

Atherosclerosis

The kinetics and morphological characteristics of the macrophage-microglial response to kainic acid-induced neuronal degeneration

Neuroscience

Mevalonate controls cytoskeleton organization and cell morphology in thyroid epithelial cells

J. Cell. Physiol.