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Apolipoprotein E receptors: linking brain development and alzheimer's disease

Abstract

Alzheimer's disease is a debilitating neurodegenerative disorder that afflicts an increasing part of our ageing population. An isoform of apolipoprotein E, a protein that mediates the transport of lipids and cholesterol in the circulatory system, predisposes carriers of this allele to the common late-onset form of the disease. How this protein is related to a neurodegenerative disorder is an enigma. Mounting evidence indicates that apolipoprotein E receptors, which are abundantly expressed in most neurons in the central nervous system, also fulfil critical functions during brain development and may profoundly influence the pathogenesis of Alzheimer's disease.

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Figure 1: The LDL receptor family in mammals, Drosophila melanogaster and Caenorhabditis elegans.
Figure 2: Hypothetical models showing interactions of cytoplasmic neuronal adaptor and scaffold proteins with the LDL receptor family and APP.
Figure 3

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Acknowledgements

Supported by grants from the NIH, the Human Frontier Science Program, the Perot Family Foundation and the American Heart Association. U.B. is supported by a fellowship from the Human Frontier Science Program.

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DATABASE LINKS

APP

tau

LDLR

ApoE

LRP

α2M

megalin

VLDLR

ApoER2

Dab1

Reelin

FE65

Cdk5

p35

p39

Ena

Vasp

Mena

FURTHER INFORMATION

The Alzheimer web

Joachim Herz's laboratory

ENCYCLOPEDIA OF LIFE SCIENCES

Alzheimer disease

Glossary

GENETIC LINKAGE

The association of two or more genes such that they are normally transmitted together.

KUNITZ-TYPE PROTEASE INHIBITOR DOMAIN

An alternatively transcribed exon within APP that encodes a protease inhibitor. APP is also known as protease nexin II, and is a potent inhibitor of blood coagulation factors IXa and XIa.

POLYMORPHISM

The existence of different genotypes in frequencies that cannot be explained by recurrent mutations.

HOLOPROSENCEPHALY

Failure of the forebrain or prosencephalon to divide into hemispheres or lobes, often accompanied by a deficit in midline facial development.

CEREBELLAR ATAXIA

Loss of muscle coordination caused by disorders of the cerebellum.

NPxY

A tetra-amino-acid motif present in the cytoplasmic tail of the LDL receptor family and other cell surface receptors mediating endocytosis and interactions with PTB-domain-containing adaptor and scaffold proteins.

WW DOMAIN

Domains containing 38–40 amino acids that bind proline-rich sequences in various proteins.

COATED PIT

An invagination of the membrane involved in receptor-mediated endocytosis.

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Herz, J., Beffert, U. Apolipoprotein E receptors: linking brain development and alzheimer's disease. Nat Rev Neurosci 1, 51–58 (2000). https://doi.org/10.1038/35036221

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