title: Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein.
abstract: Presenilin (PS) is essential for the gamma-cleavage required for the generation of the C terminus of amyloid beta-protein (Abeta). However, the mechanism underlying PS-mediated gamma-cleavage remains unclear. We have identified Herp cDNA by our newly developed screening method for the isolation of cDNAs that increase the degree of gamma-cleavage. Herp was originally identified as a homocysteine-responsive protein, and its expression is up-regulated by endoplasmic reticulum stress. Herp is an endoplasmic reticulum-localized membrane protein that has a ubiquitin-like domain. Here, we report that a high expression of Herp in cells increases the level of Abeta generation, although not in PS-deficient cells. We found that Herp interacts with both PS1 and PS2. Thus, Herp regulates PS-mediated Abeta generation, possibly through its binding to PS. Immunohistochemical analysis of a normal human brain section with an anti-Herp antibody revealed the exclusive staining of neurons and vascular smooth muscle cells. Moreover, the antibody strongly stained activated microglia in senile plaques in the brain of patients with Alzheimer disease. Taken together, Herp could be involved in Abeta accumulation, including the formation of senile plaques and vascular Abeta deposits.
authors.affiliation: Department of Dementia Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
authors.forename: Xiaorei
authors.initials: X
authors.lastname: Sai
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Shiraishi
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawaichi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000502:physiology*; D053764:Presenilin-1; D053766:Presenilin-2
chemical_list: D016229:Amyloid beta-Peptides; C485932:HERPUD1 protein, human; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2