title: ApoE4 delays dendritic spine formation during neuron development and accelerates loss of mature spines in vitro.
abstract: The ε4 allele of the gene that encodes apolipoprotein E (APOE4) is the greatest genetic risk factor for Alzheimer's disease (AD), while APOE2 reduces AD risk, compared to APOE3. The mechanism(s) underlying the effects of APOE on AD pathology remains unclear. In vivo, dendritic spine density is lower in APOE4-targeted replacement (APOE-TR) mice compared with APOE2- and APOE3-TR mice. To investigate whether this apoE4-induced decrease in spine density results from alterations in the formation or the loss of dendritic spines, the effects of neuron age and apoE isoform on the total number and subclasses of spines were examined in long-term wild-type neurons co-cultured with glia from APOE2-, APOE3- and APOE4-TR mice. Dendritic spine density and maturation were evaluated by immunocytochemistry via the presence of drebrin (an actin-binding protein) with GluN1 (NMDA receptor subunit) and GluA2 (AMPA receptor subunit) clusters. ApoE isoform effects were analyzed via a method previously established that identifies phases of spine formation (day-in-vitro, DIV10-18), maintenance (DIV18-21) and loss (DIV21-26). In the formation phase, apoE4 delayed total spine formation. During the maintenance phase, the density of GluN1+GluA2 spines did not change with apoE2, while the density of these spines decreased with apoE4 compared to apoE3, primarily due to the loss of GluA2 in spines. During the loss phase, total spine density was lower in neurons with apoE4 compared to apoE3. Thus, apoE4 delays total spine formation and may induce early synaptic dysfunction via impaired regulation of GluA2 in spines.
authors: *Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, U.S.A.
authors: Evelyn
authors: E
authors: Nwabuisi-Heath
authors: †Department of Neuroscience, Georgetown University, Washington, DC, U.S.A.
authors: G William
authors: GW
authors: Rebeck
authors: *Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, U.S.A.
authors: Mary Jo
authors: MJ
authors: Ladu
authors: *Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, U.S.A.
authors: Chunjiang
authors: C
authors: Yu
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C104722:glutamate receptor ionotropic, AMPA 2