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

Introduction: The deposition of the amyloid beta protein (A beta) in the brain is a hallmark of Alzheimer's disease (AD). Removal of A beta by A beta-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 A beta aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-A beta stages). To test the impact of the B-A beta stage on A beta immunotherapy, we treated transgenic mice expressing human amyloid precursor protein (APP) carrying the Swedish mutation (KM670/671NL; APP23) with the A beta-antibody beta 1 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 A beta plaque deposition and dendrite degeneration. Results: At 5 months of age, first A beta aggregates in APP23 brain consisted of non-modified A beta (representing B-A beta stage 1) whereas mature A beta-aggregates containing N-terminal truncated, pyroglutamate-modified A beta N3pE and phosphorylated A beta (representing B-A beta stage 3) were found at 11 months of age in both beta 1- and PBS-treated animals. Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old beta 1-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 beta 1- and PBS-treated APP23 mice sacrificed with 11 months. Conclusions: A beta antibody treatment was capable of protecting neurons from dendritic degeneration as long as A beta aggregation was absent or represented B-A beta stage 1 but had no protective or curative effect in later stages with mature A beta aggregates (B-A beta stage 3). These data indicate that the maturation stage of A beta aggregates has impact on potential treatment effects in APP23 mice.