title: Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer's disease mouse model.
abstract: Cognitive decline in Alzheimer's disease is attributed to loss of functional synapses, most likely caused by synaptotoxic, oligomeric forms of amyloid-β. Many treatment options aim at reducing amyloid-β levels in the brain, either by decreasing its production or by increasing its clearance. We quantified the effects of immunotherapy directed against oligomeric amyloid-β in Tg2576 mice, a mouse model of familial Alzheimer's disease. Treatment of 12-month-old mice with oligomer-specific (A-887755) or conformation-unspecific (6G1) antibodies for 8 weeks did not affect fibrillar plaque density or growth. We also quantified densities of DLG4 (previously known as PSD95) expressing post-synapses and synapsin expressing presynapses immunohistochemically. We found that both pre- and post-synapses were strongly reduced in the vicinity of plaques, whereas distant from plaques, in the cortex and hippocampal CA1 field, only post-synapses were reduced. Immunotherapy alleviated this synapse loss. Synapse loss was completely abolished distant from plaques, whereas it was only attenuated in the vicinity of plaques. These results suggest that fibrillar plaques may act as reservoirs for synaptotoxic, oligomeric amyloid-β and that sequestering oligomers suffices to counteract synaptic pathology. Therefore, cognitive function may be improved by immunotherapy even when the load of fibrillar amyloid remains unchanged.
authors.affiliation: 1 Centre for Neuropathology and Prion Research, Ludwig Maximilian University, Feodor-Lynen-Str. 23, 81377 Munich, Germany.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Dorostkar
authors.affiliation: 1 Centre for Neuropathology and Prion Research, Ludwig Maximilian University, Feodor-Lynen-Str. 23, 81377 Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Burgold
authors.affiliation: 2 Department of Translational Brain Research, German Centre for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str. 23, 81377 Munich, Germany.
authors.forename: Severin
authors.initials: S
authors.lastname: Filser
authors.affiliation: 3 AbbVie Deutschland GmbH and Co. KG, Neuroscience Discovery Research, Knollstrasse, 67061 Ludwigshafen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Barghorn
authors.affiliation: 4 Clemens Schoepf-Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstrasse 22, 64287 Darmstadt, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
authors.affiliation: 4 Clemens Schoepf-Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstrasse 22, 64287 Darmstadt, Germany.
authors.forename: Upendra Rao
authors.initials: UR
authors.lastname: Anumala
authors.affiliation: 3 AbbVie Deutschland GmbH and Co. KG, Neuroscience Discovery Research, Knollstrasse, 67061 Ludwigshafen, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Hillen
authors.affiliation: 3 AbbVie Deutschland GmbH and Co. KG, Neuroscience Discovery Research, Knollstrasse, 67061 Ludwigshafen, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Klein
authors.affiliation: 1 Centre for Neuropathology and Prion Research, Ludwig Maximilian University, Feodor-Lynen-Str. 23, 81377 Munich, Germany 2 Department of Translational Brain Research, German Centre for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str. 23, 81377 Munich, Germany 5 Munich Cluster of Systems Neurology (SyNergy), Ludwig Maximilian University, Schillerstraße 44, 80336 Munich, Germany jochen.herms@med.uni-muenchen.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D003072:Cognition Disorders / Q000473:pathology; D004195:Disease Models, Animal; D007167:Immunotherapy; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000473:pathology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer’s disease pathology; amyloid-β oligomers; immunotherapy