title: Loss of endophilin-B1 exacerbates Alzheimer's disease pathology.
abstract: Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1(-/-) mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1(-/-) mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1(-/-) mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.
authors.affiliation: 1 Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Wang
authors.affiliation: 1 Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kinoshita
authors.affiliation: 1 Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Kinoshita
authors.affiliation: 1 Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Takuma
authors.initials: T
authors.lastname: Uo
authors.affiliation: 2 Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.affiliation: 3 Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.affiliation: 3 Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: 4 School of Nursing, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Bilousova
authors.affiliation: 4 School of Nursing, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Gylys
authors.affiliation: 2 Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Case
authors.affiliation: 2 Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Jayadev
authors.affiliation: 5 Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 1703, USA.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: 2 Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195-6470, USA 3 Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-6470, USA.
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.affiliation: 1 Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98195-6470, USA yael@u.washington.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Morrison
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013574:Synaptosomes / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C429293:SH3GLB1 protein, human; C486100:Sh3glb1 protein, mouse
keywords: Alzheimer’s disease; apoptosis; beta-amyloid; cellular mechanisms; neuroprotection