title: Tomoregulin (TMEFF2) Binds Alzheimer's Disease Amyloid-β (Aβ) Oligomer and AβPP and Protects Neurons from Aβ-Induced Toxicity.
abstract: Amyloid-β (Aβ) protein causes neurotoxicity and its abnormal aggregation into amyloid is a pathological hallmark of Alzheimer's disease (AD). Cellular proteins able to interact with Aβ or its precursor, AβPP (amyloid-β protein precursor), may regulate Aβ production and neurotoxicity. We identified a brain-enriched type I transmembrane protein, tomoregulin (TR), that directly binds Aβ and Aβ oligomers (AβO). TR co-immunoprecipitated with Aβ and AβO in cultured cells and co-localized with amyloid plaques and intraneuronal Aβ in the 5xFAD AD mouse model. TR was also enriched in astrocytic processes reactive to amyloid plaques. Surface plasmon resonance spectroscopy studies showed that the extracellular domain of TR binds to AβO with a high affinity (KD = 76.8 nM). Electron paramagnetic resonance spectroscopy also demonstrated a physical interaction between spin-labeled Aβ and the TR extracellular domain in solution. Furthermore, TR also interacted with AβPP and enhanced its cleavage by α-secretase. Both cellular expression of TR and application of recombinant TR extracellular domain protected N2a neurons from AβO-induced neuronal death. These data provide first evidence that neuronal and astrocytic expression of TR is intimately related to Aβ metabolism and toxicity, and could be neuroprotective through its direct interaction with Aβ and AβPP.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hong
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA, USA.|Alzheimer's Disease Center, University of California Davis Medical Center, Sacramento, CA, USA.|M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA.
authors.forename: Jitka
authors.initials: J
authors.lastname: Petrlova
authors.affiliation: Biologics Research-USIC, Bayer Healthcare Pharmaceuticals, San Francisco, CA, USA.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: C Voss
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA, USA.|Alzheimer's Disease Center, University of California Davis Medical Center, Sacramento, CA, USA.|M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004578:Electron Spin Resonance Spectroscopy; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000378:metabolism*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D058225:Plaque, Amyloid / Q000473:pathology / Q000503:physiopathology; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C423567:TMEFF2 protein, human; C412455:Tmeff2 protein, mouse; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; amyloid; binding; neuroprotection; neurotoxicity; tomoregulin