title: Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation.
abstract: In Alzheimer's disease (AD), the mechanisms of neuronal loss remain largely unknown. Although tau pathology is closely correlated with neuronal loss, how its accumulation may lead to activation of neurotoxic pathways is unclear. Here we show that tau increased the levels of ubiquitinated proteins in the brain and triggered activation of the unfolded protein response (UPR). This suggested that tau interferes with protein quality control in the endoplasmic reticulum (ER). Consistent with this, ubiquitin was found to associate with the ER in human AD brains and tau transgenic (rTg4510) mouse brains, but this was not always colocalized with tau. The increased levels of ubiquitinated protein were accompanied by increased levels of phosphorylated protein kinase R-like ER kinase (pPERK), a marker that indicates UPR activation. Depleting soluble tau levels in cells and brain could reverse UPR activation. Tau accumulation facilitated its deleterious interaction with ER membrane and associated proteins that are essential for ER-associated degradation (ERAD), including valosin-containing protein (VCP) and Hrd1. Based on this, the effects of tau accumulation on ERAD efficiency were evaluated using the CD3δ reporter, an ERAD substrate. Indeed, CD3δ accumulated in both in vitro and in vivo models of tau overexpression and AD brains. These data suggest that soluble tau impairs ERAD and the result is activation of the UPR. The reversibility of this process, however, suggests that tau-based therapeutics could significantly delay this type of cell death and therefore disease progression.
authors.affiliation: Sanders-Brown Center on Aging and Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Abisambra
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.forename: John C
authors.initials: JC
authors.lastname: O'Leary
authors.forename: Qingyou
authors.initials: Q
authors.lastname: Li
authors.forename: Sarah
authors.initials: S
authors.lastname: Brady
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Chantal E
authors.initials: CE
authors.lastname: Guidi
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Nordhues
authors.forename: Matthew
authors.initials: M
authors.lastname: Cockman
authors.forename: Amirthaa
authors.initials: A
authors.lastname: Suntharalingham
authors.forename: Pengfei
authors.initials: P
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Atkins
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D001923:Brain Chemistry; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D004721:Endoplasmic Reticulum / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*; D019892:eIF-2 Kinase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; D025801:Ubiquitin; D019892:eIF-2 Kinase; D016875:tau Proteins