Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

The beta-secretase cleaved A beta-bearing carboxy-terminal fragments (beta CTFs) of amyloid precursor protein (APP) in neural cells have been suggested to be cytotoxic. However, the functional significance of beta CTFs in vivo remains elusive. We created a transgenic mouse line beta CTF99/B6 expressing the human beta CTF99 in the brain of inbred C57BL/6 strain. Tg-beta CTF99/B6 mouse brain at 12-16 months showed severely down-regulated calbindin, phospho-CREB, and Bel-x(L) expression and up-regulated phospho-JNK, Bcl-2, and Bax expression. Neuronal cell density in the Tg-beta CTF99/B6 cerebral cortex at 16-18 months was lower than that of the non-transgenic control, but not at 5 months. At 11-14 months, Tg-beta CTF99/B6 mice displayed cognitive impairments and increased anxiety, which were not observed at 5 months. These results suggest that increased beta CTF99 expression is highly detrimental to the aging brain and that it produces a progressive and age-dependent AD-like pathogenesis. (c) 2005 Elsevier Inc. All rights reserved.