Characterization of a Novel Mouse Model of Alzheimer's Disease-Amyloid Pathology and Unique [beta]-Amyloid Oligomer Profile

Amyloid plaques composed of [beta]-amyloid (A[beta]) protein are a pathological hallmark of Alzheimer's disease. We here report the generation and characterization of a novel transgenic mouse model of A[beta] toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and London mutations (APP.sub.NLI) linked to familial Alzheimer's disease, under the control of a tetracycline-response element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase II[alpha]. In these mice, APP.sub.NLI is expressed at a level four-fold that of endogenous mouse APP and its expression is restricted to forebrain regions. Transgene expression was suppressed by 87% after two months of doxycycline administration. Histologically, we showed that (1) A[beta] plaques emerged in cerebral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition progressed in an age-dependent manner, occupying up to 19% of cortex at ~25 months of age; and (3) neuropathology-such as abnormal neuronal architecture, tau hyperphosphorylation and misfolding, and neuroinflammation-was observed in the vicinity of neuritic plaques. Biochemically, we determined total A[beta] production at varied ages of mice, and we showed that mice produced primarily fibrillar A[beta] assemblies recognized by conformation-selective OC antibodies, but few non-fibrillar oligomers (e.g., A[beta]*56) detectable by A11 antibodies. Finally, we showed that expression of the tetracycline transactivator resulted in reduced brain weight and smaller dentate-gyrus size. Collectively, these data indicate that rTg9191 mice may serve as a model for studying the neurological effects of the fibrillar A[beta] assemblies in situ.