ApoE receptor 2 controls neuronal survival in the adult brain.
A central pathogenic feature of neurodegenerative diseases and neurotrauma is the death of neurons. A mechanistic understanding of the factors and conditions that induce the dysfunction and death of neurons is essential for devising effective treatment strategies against neuronal loss after trauma or during aging. Because Apolipoprotein E (ApoE) is a major risk factor for several neurodegenerative diseases, including Alzheimer's disease , a direct or indirect role of ApoE receptors in the disease process is likely. Here we have used gene targeting in mice to investigate possible roles of ApoE receptors in the regulation of neuronal survival. We demonstrate that a differentially spliced isoform of an ApoE receptor, ApoE receptor 2 (Apoer2), is essential for protection against neuronal cell loss during normal aging. Furthermore, the same splice form selectively promotes neuronal cell death after injury through mechanisms that may involve serine/threonine kinases of the Jun N-terminal kinase (JNK) family. These findings raise the possibility that ApoE and its receptors cooperatively regulate common mechanisms that are essential to neuronal survival in the adult brain.
Beffert
Uwe
U
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Nematollah Farsian
Farnas
F
Masiulis
Irene
I
Hammer
Robert E
RE
Yoon
Sung Ok
SO
Giehl
Klaus M
KM
Herz
Joachim
J
D000375:Aging; D017398:Alternative Splicing; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000502:physiology*; D016923:Cell Death; D002470:Cell Survival; D005091:Exons; D026502:LDL-Receptor Related Proteins; D051379:Mice; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D017434:Protein Structure, Tertiary; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D026502:LDL-Receptor Related Proteins; D018110:Receptors, Lipoprotein; C098773:low density lipoprotein receptor-related protein 8; D048057:Mitogen-Activated Protein Kinase 10