title: Impact of amyloid β aggregate maturation on antibody treatment in APP23 mice.
abstract: BACKGROUND
  The deposition of the amyloid β protein (Aβ) in the brain is a hallmark of Alzheimer's disease (AD). Removal of Aβ by Aβ-antibody treatment has been developed as a potential treatment strategy against AD. First clinical trials showed neither a stop nor a reduction of disease progression. Recently, we have shown that the formation of soluble and insoluble Aβ aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-Aβ stages). To test the impact of the B-Aβ stage on Aβ immunotherapy, we treated transgenic mice expressing human amyloid precursor protein (APP) carrying the Swedish mutation (KM670/671NL; APP23) with the Aβ-antibody β1 or phosphate-buffered saline (PBS) beginning 1) at 3 months, before the onset of dendrite degeneration and plaque deposition, and 2) at 7 months, after the start of Aβ plaque deposition and dendrite degeneration.
  
  
  RESULTS
  At 5 months of age, first Aβ aggregates in APP23 brain consisted of non-modified Aβ (representing B-Aβ stage 1) whereas mature Aβ-aggregates containing N-terminal truncated, pyroglutamate-modified AβN3pE and phosphorylated Aβ (representing B-Aβ stage 3) were found at 11 months of age in both β1- and PBS-treated animals. Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old β1-treated animals sacrificed at 5 months. When treatment started at 7 months of age, no differences in the numbers of healthy commissural neurons were observed between β1- and PBS-treated APP23 mice sacrificed with 11 months.
  
  
  CONCLUSIONS
  Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ aggregation was absent or represented B-Aβ stage 1 but had no protective or curative effect in later stages with mature Aβ aggregates (B-Aβ stage 3). These data indicate that the maturation stage of Aβ aggregates has impact on potential treatment effects in APP23 mice.
authors.affiliation: Institute of Pathology - Laboratory of Neuropathology, Center of Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, D-89081, Ulm, Germany.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Balakrishnan
authors.affiliation: Institute of Pathology - Laboratory of Neuropathology, Center of Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, D-89081, Ulm, Germany.
authors.forename: Ajeet
authors.initials: A
authors.lastname: Rijal Upadhaya
authors.affiliation: Institute of Pathology - Laboratory of Neuropathology, Center of Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, D-89081, Ulm, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Steinmetz
authors.affiliation: Novartis Pharma, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Reichwald
authors.affiliation: Novartis Pharma, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.affiliation: Institute for Pharmaceutical Biotechnology, Center of Biomedical Research, University of Ulm, Ulm, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
authors.affiliation: Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Gunma University School of Health Sciences, Maebashi, Gunma, Japan.
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.affiliation: Novartis Pharma, Novartis Institutes for Biomedical Research, Basel, Switzerland.|Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: Institute of Pathology - Laboratory of Neuropathology, Center of Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, D-89081, Ulm, Germany. dietmar.thal@uni-ulm.de.
authors.forename: Dietmar Rudolf
authors.initials: DR
authors.lastname: Thal
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000276:immunology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D047468:Immunoprecipitation; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D014611:Vaccination / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies