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Impact of amyloid beta aggregate maturation on antibody treatment in APP23 mice

Balakrishnan, Karthikeyan and Upadhaya, Ajeet Rijal and Steinmetz, Julia and Abramowski, Dorothee and Faendrich, Marcus and Kumar, Satish and Yamaguchi, Haruyasu and Walter, Jochen and Staufenbiel, Matthias and Thal, Dietmar R (2015) Impact of amyloid beta aggregate maturation on antibody treatment in APP23 mice. Acta Neuropathol Comm., 3 (1). p. 41.

Abstract

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. The formation of soluble and insoluble Aβ aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-Aβ stages) including non-modified and modified forms of Aβ. 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. At 5 months of age, first Aβ aggregates in APP23 brain consisted of non-modified Aβ whereas mature Aβ-aggregates containing N-terminal truncated, pyroglutamate-modified and phosphorylated Aβ 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. Taken together, Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ was absent or exhibited Aβ aggregates in an initial maturation stage but had no protective or curative effect in later stages with mature Aβ aggregates. These data indicate that the maturation stage of Aβ aggregates has an impact on potential treatment effects.

Item Type: Article
Keywords: amyloid, immunization, antibody,protofibrils,fibrils,clearance
Date Deposited: 15 Oct 2015 23:45
Last Modified: 15 Oct 2015 23:45
URI: https://oak.novartis.com/id/eprint/25546

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