title: Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease.
abstract: Pathological features in Alzheimer's brains include mitochondrial dysfunction and dystrophic neurites (DNs) in areas surrounding amyloid plaques. Using a mouse model that overexpresses reticulon 3 (RTN3) and spontaneously develops age-dependent hippocampal DNs, here we report that DNs contain both RTN3 and REEPs, topologically similar proteins that can shape tubular endoplasmic reticulum (ER). Importantly, ultrastructural examinations of such DNs revealed gradual accumulation of tubular ER in axonal termini, and such abnormal tubular ER inclusion is found in areas surrounding amyloid plaques in biopsy samples from Alzheimer's disease (AD) brains. Functionally, abnormally clustered tubular ER induces enhanced mitochondrial fission in the early stages of DN formation and eventual mitochondrial degeneration at later stages. Furthermore, such DNs are abrogated when RTN3 is ablated in aging and AD mouse models. Hence, abnormally clustered tubular ER can be pathogenic in brain regions: disrupting mitochondrial integrity, inducing DNs formation and impairing cognitive function in AD and aging brains.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Sharoar
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Y
authors.identifier: 0000-0002-6547-0172
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.affiliation: The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Perry
authors.affiliation: Department of Pathology, Case Western University School of Medicine, Cleveland, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Yan
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons; D001921:Brain / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000473:pathology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C482720:Rtn3 protein, mouse; D053829:Amyloid Precursor Protein Secretases