title: Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP.
abstract: Reducing levels of the aggregation-prone Aβ peptide that accumulates in the brain with Alzheimer's disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of Aβ. To date, the physiological state of Aβ in brain remains unclear, since the available methods used to process brain tissue for determination of Aβ aggregate conformation can in themselves alter the structure and/or composition of the aggregates. Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Aβ and amyloid precursor protein (APP) in brain of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal Aβ aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of Aβ and APP that occur prior to plaque formation may provide novel targets for AD therapy.
authors.affiliation: Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Klementieva
authors.affiliation: Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Willén
authors.affiliation: Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Martinsson
authors.affiliation: Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Israelsson
authors.affiliation: MAX IV Laboratory, Lund University, 22100 Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Engdahl
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cladera
authors.affiliation: MAX IV Laboratory, Lund University, 22100 Lund, Sweden.|Chemical Physics, Department of Chemistry, Lund University, 22100 Lund, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Uvdal
authors.affiliation: Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors.forename: G K
authors.initials: GK
authors.lastname: Gouras
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D063347:Native Polyacrylamide Gel Electrophoresis; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D017729:Presynaptic Terminals; D061251:Primary Cell Culture; D066329:Protein Aggregates; D011487:Protein Conformation; D017550:Spectroscopy, Fourier Transform Infrared; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D017356:Synchrotrons
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009479:Neuropeptides; D010446:Peptide Fragments; D066329:Protein Aggregates; D016708:Synaptophysin; C569015:Syp protein, mouse; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C053386:drebrins