title: Accumulation of murine amyloid-β mimics early Alzheimer's disease.
abstract: Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for <1% of all patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer's disease genes.
authors.affiliation: 1 Translational Neurodegeneration Research and Neuropathology Lab, Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway 2 Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krohn
authors.affiliation: 3 Department of Anatomy, University of Greifswald, Greifswald, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bracke
authors.affiliation: 4 Department of Physiology, University of Rostock, Rostock, Germany.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Avchalumov
authors.affiliation: 2 Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Schumacher
authors.affiliation: 2 Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hofrichter
authors.affiliation: 1 Translational Neurodegeneration Research and Neuropathology Lab, Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway 2 Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Paarmann
authors.affiliation: 2 Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Fröhlich
authors.affiliation: 2 Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Lange
authors.affiliation: 1 Translational Neurodegeneration Research and Neuropathology Lab, Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway 2 Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
authors.affiliation: 3 Department of Anatomy, University of Greifswald, Greifswald, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen Und Halbach
authors.affiliation: 1 Translational Neurodegeneration Research and Neuropathology Lab, Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway 2 Department of Neurology, University of Rostock, Rostock, Germany 5 University of Lübeck, LIED, Lübeck, Germany 6 Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle, Germany jens.pahnke@medisin.uio.no.
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D060825:Cognitive Dysfunction / Q000235:genetics; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D015260:Neprilysin / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015260:Neprilysin; C421109:multidrug resistance-associated protein 1
keywords: ABCB1; ABCC1; Alzheimer’s disease; MCI; amyloidosis; neprilysin