title: Inhibition of amyloid-β plaque formation by α-synuclein.
abstract: Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.
authors.affiliation: Adolf Butenandt Institute, Department of Biochemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Bachhuber
authors.affiliation: 1] Neurocenter, Department of Neurology, University of Freiburg, Freiburg, Germany. [2] Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Katzmarski
authors.affiliation: Adolf Butenandt Institute, Department of Biochemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Joanna F
authors.initials: JF
authors.lastname: McCarter
authors.affiliation: Neurocenter, Department of Neurology, University of Freiburg, Freiburg, Germany.
authors.forename: Desiree
authors.initials: D
authors.lastname: Loreth
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.affiliation: Department of Metabolic Biochemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Frits
authors.initials: F
authors.lastname: Kamp
authors.affiliation: Adolf Butenandt Institute, Department of Biochemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Abou-Ajram
authors.affiliation: Department of Metabolic Biochemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nuscher
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Serrano-Pozo
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Müller
authors.affiliation: 1] Institute of Neuropathology, University of Freiburg, Freiburg, Germany. [2] Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: 1] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. [2] Department of Metabolic Biochemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: 1] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. [2] Department of Metabolic Biochemistry, Ludwig-Maximilians University, Munich, Germany. [3] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: 1] Adolf Butenandt Institute, Department of Biochemistry, Ludwig-Maximilians University, Munich, Germany. [2] Neurocenter, Department of Neurology, University of Freiburg, Freiburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Meyer-Luehmann
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D053764:Presenilin-1 / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins