title: Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors.
abstract: Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer disease (AD) and likely contributes to neuropathology through various pathways. Here we report that the intracellular trafficking of apoE4 is impaired in Neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. In Neuro-2a cells, more apoE4 than apoE3 molecules remained immobilized in the endoplasmic reticulum (ER) and the Golgi apparatus, and the lateral motility of apoE4 was significantly lower in the Golgi apparatus (but not in the ER) than that of apoE3. Likewise, the immobile fraction was larger, and the lateral motility was lower for apoE4 than apoE3 in mouse primary hippocampal neurons. ApoE4 with the R61T mutation, which abolishes apoE4 domain interaction, was less immobilized, and its lateral motility was comparable with that of apoE3. The trafficking impairment of apoE4 was also rescued by disrupting domain interaction with the small-molecule structure correctors GIND25 and PH002. PH002 also rescued apoE4-induced impairments of neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons. ApoE4 did not affect trafficking of amyloid precursor protein, another AD-related protein, through the secretory pathway. Thus, domain interaction renders more newly synthesized apoE4 molecules immobile and slows their trafficking along the secretory pathway. Correcting the pathological structure of apoE4 by disrupting domain interaction is a potential therapeutic approach to treat or prevent AD related to apoE4.
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
authors: Jens
authors: J
authors: Brodbeck
authors: Jim
authors: J
authors: McGuire
authors: Zhaoping
authors: Z
authors: Liu
authors: Anke
authors: A
authors: Meyer-Franke
authors: Maureen E
authors: ME
authors: Balestra
authors: Dah-eun
authors: DE
authors: Jeong
authors: Mike
authors: M
authors: Pleiss
authors: Casey
authors: C
authors: McComas
authors: Fred
authors: F
authors: Hess
authors: David
authors: D
authors: Witter
authors: Scott
authors: S
authors: Peterson
authors: Matthew
authors: M
authors: Childers
authors: Mark
authors: M
authors: Goulet
authors: Nigel
authors: N
authors: Liverton
authors: Richard
authors: R
authors: Hargreaves
authors: Stephen
authors: S
authors: Freedman
authors: Karl H
authors: KH
authors: Weisgraber
authors: Robert W
authors: RW
authors: Mahley
authors: Yadong
authors: Y
authors: Huang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000378:metabolism*; D001692:Biological Transport; D002460:Cell Line; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D036681:Fluorescence Recovery After Photobleaching; D006056:Golgi Apparatus / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4