Cai_2012_Neurotox.Res_21_160

beta-amyloid precursor protein (APP) and presenilins mutations cause early-onset familial Alzheimer's disease (FAD). Some FAD-based mouse models produce amyloid plaques, others do not. beta-Amyloid (Abeta) deposition can manifest as compact and diffuse plaques; it is unclear why the same Abeta molecules aggregate in different patterns. Is there a basic cellular process governing Abeta plaque pathogenesis? We showed in some FAD mouse models that compact plaque formation is associated with a progressive axonal pathology inherent with increased expression of beta-secretase (BACE1), the enzyme initiating the amyloidogenic processing of APP. A monoclonal Abeta antibody, 3D6, visualized distinct axon terminal labeling before plaque onset. The present study was set to understand BACE1 and axonal changes relative to diffuse plaque development and to further characterize the novel axonal Abeta antibody immunoreactivity (IR), using triple transgenic AD (3xTg-AD) mice as experimental model. Diffuse-like plaques existed in the forebrain in aged transgenics and were regionally associated with increased BACE1 labeled swollen/sprouting axon terminals. Increased BACE1/3D6 IR at axon terminals occurred in young animals before plaque onset. These axonal elements were also co-labeled by other antibodies targeting the N-terminal and mid-region of Abeta domain and the C-terminal of APP, but not co-labeled by antibodies against the Abeta C-terminal and APP N-terminal. The results suggest that amyloidogenic axonal pathology precedes diffuse plaque formation in the 3xTg-AD mice, and that the early-onset axonal Abeta antibody IR in transgenic models of AD might relate to a cross-reactivity of putative APP beta-carboxyl terminal fragments.