title: Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice.
abstract: Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology and.
authors.forename: Johanna
authors.initials: J
authors.lastname: Knoferle
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-3882-9829
authors.initials: D
authors.lastname: Walker
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology and.
authors.forename: Laura
authors.initials: L
authors.lastname: Leung
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Biomedical Science Program, University of California, San Francisco, California 94143.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Gillespie
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Biomedical Science Program, University of California, San Francisco, California 94143.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Tong
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology and.
authors.forename: Nga
authors.initials: N
authors.lastname: Bien-Ly
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology and Biomedical Science Program, University of California, San Francisco, California 94143, Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, and Department of Pathology, University of California, San Francisco, California 94143 yhuang@gladstone.ucsf.edu.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4 / Q000096:biosynthesis*; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D007858:Learning / Q000502:physiology*; D008569:Memory Disorders / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D053327:Apolipoprotein E4
keywords: GABAergic interneuron; apoE; astrocyte; conditional knock-out mice; learning and memory