title: Impaired Autophagy in APOE4 Astrocytes.
abstract: Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Simonovitch
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Schmukler
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Alina
authors.initials: A
authors.lastname: Bespalko
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Iram
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Frenkel
authors.affiliation: Washington University School of Medicine, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, St. Louis, MO, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neuroscience, University of California at San Diego, San Diego, CA, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Danny M
authors.initials: DM
authors.lastname: Michaelson
authors.affiliation: Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Pinkas-Kramarski
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D002491:Central Nervous System Agents; D002738:Chloroquine; D020123:Sirolimus
keywords: Alzheimer’s disease; amyloid-β; apolipoprotein E4; autophagy