Intracellular accumulation of detergent-soluble amyloidogenic A beta fragment of Alzheimer's disease precursor protein in the hippocampus of aged transgenic mice

To study amyloid beta-protein (A beta) production and aggregation in vivo, we created two transgenic (Tg) mouse lines expressing the C-terminal 100 am ino acids of human amyloid precursor protein (APP): Tg C100.V717F and Tg C1 00,WT. Western blot analysis showed that human APP-C100 and A beta were pro duced in brain and some peripheral tissues and A beta was produced in serum . Using antibodies specific for the A beta C terminus we found that Tg C100 .V717F produced a 1.6-fold increase in A beta 42/A beta 40 compared with Tg C100.WT. Approximately 30% of total brain A beta (similar to 122 ng/g of w et tissue) was water-soluble. The remaining 70% of A beta partitioned into the particulate fraction and was completely sodium dodecyl sulfate-soluble, In contrast, human Alzheimer's disease brain has predominantly sodium dode cyl sulfate-insoluble A beta. Immunohistochemistry with an A beta(5-8) anti body showed that A beta or A beta-containing fragments accumulated intracel lularly in the hippocampus of aged Tg C100.V717F mice. The soluble A beta l evels in Tg brain are similar to those in normal human brain, and this may explain the lack of microscopic amyloid deposits in the Tg mice. However, t his mouse model provides a system to study the intracellular processing and accumulation of A beta or A beta-containing fragments and to screen for co mpounds directed at the gamma-secretase activity.