title: Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner.
abstract: Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low-density lipoprotein receptor (LDLR) has a high affinity for apoE, and is the only member of its receptor family to demonstrate an apoE isoform specific binding affinity (E4>E3>>E2). Evidence suggests that a functional interaction between apoE and LDLR influences the risk of CVD and AD. We hypothesize that the differential cognitive effects of the apoE isoforms are a direct result of their varying interactions with LDLR. To test this hypothesis, we have employed transgenic mice that express human apoE2, apoE3, or apoE4, and either human LDLR (hLDLR) or no LDLR (LDLR(-/-)). Our results show that plasma and brain apoE levels, cortical cholesterol, and spatial memory are all regulated by isoform-dependent interactions between apoE and LDLR. Conversely, both anxiety-like behavior and cued associative memory are strongly influenced by APOE genotype, but these processes appear to occur via an LDLR-independent mechanism. Both the lack of LDLR and the interaction between E4 and the LDLR were associated with significant impairments in the retention of long term spatial memory. Finally, levels of hippocampal apoE correlate with long term spatial memory retention in mice with human LDLR. In summary, we demonstrate that the apoE-LDLR interaction affects regional brain apoE levels, brain cholesterol, and cognitive function in an apoE isoform-dependent manner.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Johnson
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Reid H J
authors.initials: RH
authors.lastname: Olsen
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Merkens
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University (OHSU), Portland, OR, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: DeBarber
authors.affiliation: Departments of Pediatrics and Molecular and Medical Genetics, Institute on Development and Disability, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR, USA; Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Steiner
authors.affiliation: Department of Medicine, Duke University, Durham VA Medical Center and GRECC, Durham, NC, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA; Departments of Neurology and Radiation Medicine, Oregon Health & Science University, Portland, OR, USA; Division of Neuroscience, ONPRC, Oregon Health & Science University, Beaverton, OR, USA. Electronic address: raberj@ohsu.edu.
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D053329:Apolipoprotein E2 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D053318:Apolipoprotein E3 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D003213:Conditioning, Psychological / Q000502:physiology; D006801:Humans; D008568:Memory / Q000502:physiology; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013028:Space Perception / Q000502:physiology*
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; C573412:LDLR protein, human; D011973:Receptors, LDL; D002784:Cholesterol
keywords: Alzheimer's; Apolipoprotein E; Cholesterol; Hippocampus; LDLR; Low density lipoprotein receptor; Memory; apoE